Patent application title: HUMAN ANTIBODIES TO HUMAN DELTA LIKE LIGAND 4
Inventors:
Nicholas J. Papadopoulos (Lagrangeville, NY, US)
Joel H. Martin (Putnam Valley, NY, US)
Eric Smith (New York, NY, US)
Eric Smith (New York, NY, US)
Irene Noguera-Troise (Bay Shore, NY, US)
Gavin Thurston (White Plains, NY, US)
Gavin Thurston (White Plains, NY, US)
Assignees:
Regeneron Pharmaceuticals, Inc.
IPC8 Class: AA61K39395FI
USPC Class:
4241391
Class name: Drug, bio-affecting and body treating compositions immunoglobulin, antiserum, antibody, or antibody fragment, except conjugate or complex of the same with nonimmunoglobulin material binds antigen or epitope whose amino acid sequence is disclosed in whole or in part (e.g., binds specifically-identified amino acid sequence, etc.)
Publication date: 2009-06-04
Patent application number: 20090142354
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Patent application title: HUMAN ANTIBODIES TO HUMAN DELTA LIKE LIGAND 4
Inventors:
Nicholas J. Papadopoulos
Joel H. Martin
Eric Smith
Irene Noguera-Troise
Gavin Thurston
Agents:
REGENERON PHARMACEUTICALS, INC
Assignees:
Regeneron Pharmaceuticals, Inc.
Origin: TARRYTOWN, NY US
IPC8 Class: AA61K39395FI
USPC Class:
4241391
Abstract:
An isolated human antibody or a fragment of a human antibody which
specifically binds to human delta-like ligand 4 (hDll4) and blocks hDll4
binding to a Notch receptor. The human anti-hDll4 antibody or antibody
fragment binds dimeric hDll4 with an affinity of 75 pM or better, as
measured by surface plasmon resonance.Claims:
1. A human antibody or antibody fragment which specifically binds human
delta-like 4 (hDll4), comprising heavy-chain CDR1, CDR2 and CDR3, which
comprise the amino acid sequences of SEQ ID NOS:399, 401 and 403,
respectively, and light-chain CDR1, CDR2 and CDR3, which comprise the
amino acid sequences of SEQ ID NOS:407, 409 and 411, respectively,
wherein said antibody or antibody fragment binds an epitope within the
N-terminal domain of hDll4.
2. The human antibody or antibody fragment of claim 1 being capable of binding dimeric hDll4 with an affinity constant (KD) of about 75 pM or less, as measured by surface plasmon resonance.
3. A human antibody or antibody fragment which specifically binds hDll4, comprising a heavy-chain variable region comprising the amino acid sequence of SEQ ID NO:397, and a light-chain variable region comprising the amino acid sequence of SEQ ID NO:405, wherein said antibody or antibody fragment binds an epitope within the N-terminal domain of hDll4.
4. The human antibody or antibody fragment of claim 3 being capable of binding dimeric hDll4 with a KD of about 75 pM or less, as measured by surface plasmon resonance.
5. A pharmaceutical composition comprising the antibody or antibody fragment of claim 1 and a pharmaceutically acceptable carrier.
6. A pharmaceutical composition comprising the antibody or antibody fragment of claim 3 and a pharmaceutically acceptable carrier.
Description:
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001]This application is a continuation of U.S. non-provisional application Ser. No. 12/002,245 filed Dec. 14, 2007, which claims the benefit under 35 U.S.C § 119(e) of U.S. provisional application Nos. 60/874,922 filed Dec. 14, 2006, 60/916,415 filed May 7, 2007, and 60/985,323 filed Nov. 5, 2007, all of which are herein specifically incorporated by reference in their entirety.
BACKGROUND
[0002]The Notch-signaling pathway is a system for cell-to-cell communication used by a wide range of eukaryotes for many biological processes, such as differentiation, proliferation, and homeostasis. Delta like 4 (Dl4) or delta-like ligand 4 (Dll4) (hereinafter "Dll4") is a member of the Delta family of Notch ligands which exhibits highly selective expression by vascular endothelium (Shutter et al. (2000) Genes Develop. 14:1313-1318). Dll4 is a ligand for Notch receptors, including Notch 1 and Notch 4. The nucleic acid and amino acid sequences for human Dll4 are shown in SEQ ID NO:1-2, respectively.
[0003]Methods to produce antibodies useful as human therapeutics include generation of chimeric antibodies and humanized antibodies (see, for example, U.S. Pat. No. 6,949,245). See, for example, WO 94/02602 (Abgenix) and U.S. Pat. No. 6,596,541 (Regeneron Pharmaceuticals), which publications are herein specifically incorporated by reference, describing methods of generating nonhuman transgenic mice capable of producing human antibodies.
[0004]Japanese patent application 2003/047470A2 (Asahi Kasei Kogyo) describes antibodies to the extracellular portion of human Notch ligand protein.
BRIEF SUMMARY OF THE INVENTION
[0005]In a first aspect, the invention provides human antibodies, preferably recombinant human antibodies, that specifically bind human delta-like ligand 4 (hDll4). These antibodies are characterized by binding to hDll4 with high affinity and by the ability to neutralize Dll4 activity. The antibodies of the invention are capable of blocking Dll4 binding to its Notch receptor(s), and thus inhibit signaling by Dll4. The antibodies can be full-length (for example, an IgG1 or IgG4 antibody) or may comprise only an antigen-binding portion (for example, a Fab, F(ab')2 or scFv fragment), and may be modified to effect functionality, e.g., to eliminate residual effector functions (Glu which eliminates residual effector functions (Reddy et al. (2000) J. Immunol. 164:1925-1933).
[0006]In one embodiment, the antibody of the invention comprises a heavy chain variable region (HCVR) selected from the group consisting of SEQ ID NO:4, 20, 36, 52, 68, 84, 100, 116, 132, 148, 164, 180, 196, 212, 228, 244, 260, 276, 292, 308, 324, 340, 356, 372, 397, 413, 429, 445, 461, 477, 493, 509, 525, 541, 557, 573, 589, 605, 621, 637, 653, 669, 685, 701, 717, 733, 749, 765, 781, 797, 813, 893, 897, 901, 905, 909, 913, 917, 921, 925, 935, 939, 943, and 947 or a substantially identical sequence thereof. In a preferred embodiment, the HCVR is the amino acid sequence of SEQ ID NO:429 or 901.
[0007]In one embodiment, the antibody of the invention comprises a light chain variable region (LCVR) selected from the group consisting of SEQ ID NO:12, 28, 44, 60, 76, 92, 108, 124, 140, 156, 172, 188, 204, 220, 236, 252, 268, 284, 300, 316, 332, 348, 364, 380, 405, 421, 437, 453, 469, 485, 501, 517, 533, 549, 565, 581, 597, 613, 629, 645, 661, 677, 693, 709, 725, 741, 757, 773, 789, 805, 821, 895, 899, 903, 907, 911, 915, 919, 923, 927, 937, 941, 945, and 949 or a substantially identical sequence thereof. In a preferred embodiment, the LCVR is the amino acid sequence of SEQ ID NO:437 or 903.
[0008]In one embodiment, the antibody of the invention comprises a HCVR selected from the group consisting of SEQ ID NO: 4, 20, 36, 52, 68, 84, 100, 116, 132, 148, 164, 180, 196, 212, 228, 244, 260, 276, 292, 308, 324, 340, 356, 372, 397, 413, 429, 445, 461, 477, 493, 509, 525, 541, 557, 573, 589, 605, 621, 637, 653, 669, 685, 701, 717, 733, 749, 765, 781, 797, 813, 893, 897, 901, 905, 909, 913, 917, 921, 925, 935, 939, 943, and 947 or a substantially identical sequence thereof, and a LCVR selected from the group consisting of SEQ ID NO:12, 28, 44, 60, 76, 92, 108, 124, 140, 156, 172, 188, 204, 220, 236, 252, 268, 284, 300, 316, 332, 348, 364, 380, 405, 421, 437, 453, 469, 485, 501, 517, 533, 549, 565, 581, 597, 613, 629, 645, 661, 677, 693, 709, 725, 741, 757, 773, 789, 805, 821, 895, 899, 903, 907, 911, 915, 919, 923, 927, 937, 941, 945, and 949 or a substantially identical sequence thereof. In a preferred embodiment, the HCVR/LCVR are the amino acid sequence pairs SEQ ID NO:429/437 or 901/903.
[0009]In one embodiment, the invention features a human antibody or antibody fragment comprising a heavy chain complementary determining region 1 (CDR1) selected from the group consisting of SEQ ID NO:6, 22, 38, 54, 70, 86, 102, 118, 134, 150, 166, 182, 198, 214, 230, 246, 262, 278 294, 310, 326, 342, 358, 374, 399, 415, 431, 447, 463, 479, 495, 511, 527, 543, 559, 575, 591, 607, 623, 639, 655, 671, 687, 703, 719, 735, 751, 767, 783, 799, 815, 831, 847, 863 and 879, or a substantially identical sequence thereof.
[0010]In one embodiment, the invention features a human antibody or antibody fragment comprising a heavy chain CDR2 selected from the group consisting of SEQ ID NO:8, 24, 40, 56, 72, 88, 104, 120, 136, 152, 168, 184, 200, 216, 232, 248, 264, 280, 296, 312, 328, 344, 360, 376, 401, 417, 433, 449, 465, 481, 497, 513, 529, 545, 561, 577, 593, 609, 625, 641, 657, 673, 689, 705, 721, 737, 753, 769, 785, 801, 817, 833, 849, 865 and 881, or a substantially identical sequence thereof.
[0011]In one embodiment, the invention features a human antibody or antibody fragment comprising a heavy chain CDR3 selected from the group consisting of SEQ ID NO:10, 26, 42, 58, 74, 90, 106, 122, 138, 154, 170, 186, 202, 218, 234, 250, 266, 282, 298, 314, 330, 346, 362, 378, 403, 419, 435, 451, 467, 483, 499, 515, 531, 547, 563, 579, 595, 611, 627, 643, 659, 675, 691, 707, 723, 739, 755, 771, 787, 803, 819, 835, 851, 867 and 883, or a substantially identical sequence thereof.
[0012]In one embodiment, the invention features a human antibody or antibody fragment comprising a heavy chain CDR1 selected from the group consisting of SEQ ID NO: 6, 22, 38, 54, 70, 86, 102, 118, 134, 150, 166, 182, 198, 214, 230, 246, 262, 278 294, 310, 326, 342, 358, 374, 399, 415, 431, 447, 463, 479, 495, 511, 527, 543, 559, 575, 591, 607, 623, 639, 655, 671, 687, 703, 711119, 735, 751, 767, 783, 799, 815, 831, 847, 863 and 879, or a substantially identical sequence thereof; a heavy chain CDR2 selected from the group consisting of SEQ ID NO: 8, 24, 40, 56, 72, 88, 104, 120, 136, 152, 168, 184, 200, 216, 232, 248, 264, 280, 296, 312, 328, 344, 360, 376, 401, 417, 433, 449, 465, 481, 497, 513, 529, 545, 561, 577, 593, 609, 625, 641, 657, 673, 689, 705, 721, 737, 753, 769, 785, 801, 817, 833, 849, 865 and 881, or a substantially identical sequence thereof; and a heavy chain CDR3 selected from the group consisting of SEQ ID NO: 10, 26, 42, 58, 74, 90, 106, 122, 138, 154, 170, 186, 202, 218, 234, 250, 266, 282, 298, 314, 330, 346, 362, 378, 403, 419, 435, 451, 467, 483, 499, 515, 531, 547, 563, 579, 595, 611, 627, 643, 659, 675, 691, 707, 723, 739, 755, 771, 787, 803, 819, 835, 851, 867 and 883, or a substantially identical sequence thereof. In a preferred embodiment, the antibody or antibody fragment comprises heavy chain CDR1, CDR2 and CDR3 selected from the group consisting of SEQ ID NO:431/433/435; 374/376/378; 783/785/787; and 799/801/803.
[0013]In one embodiment, the invention features a human antibody or antibody fragment comprising a light chain CDR1 selected from the group consisting of SEQ ID NO: 14, 30, 46, 62, 78, 94, 110, 126, 142, 158, 174, 190, 206, 222, 238, 254, 270, 286, 302, 318, 334, 350, 366, 382, 407, 423, 439, 455, 471, 487, 503, 519, 535, 551, 567, 583, 599, 615, 631, 647, 663, 679, 695, 711, 727, 743, 759, 775, 791, 807, 823, 839, 855, 871 and 887, or a substantially identical sequence thereof.
[0014]In one embodiment, the invention features a human antibody or antibody fragment comprising a light chain CDR2 selected from the group consisting of SEQ ID NO:16, 32, 48, 64, 80, 96, 112, 128, 144, 160, 176, 192, 208, 224, 240, 256, 272, 288, 304, 320, 336, 352, 368, 384, 409. 425, 441, 457, 473, 489, 505, 521, 537, 553, 569, 585, 601, 617, 633, 649, 665, 681, 697, 713, 729, 745, 761, 777, 793, 809, 825, 841, 857, 873 and 889, or a substantially identical sequence thereof.
[0015]In one embodiment, the invention features a human antibody or antibody fragment comprising a light chain CDR3 selected from the group consisting of SEQ ID NO:18, 34, 50, 66, 82, 98, 11, 130, 146, 162, 178, 194, 210, 226, 242, 258, 274, 290, 306, 322, 338, 354, 370, 386, 411, 427, 443, 459, 475, 491, 507, 523, 539, 555, 571, 587, 603, 619, 635, 651, 667, 683, 699, 715, 731, 747, 763, 779, 795, 811, 827, 843, 859, 875 and 891, or a substantially identical sequence thereof.
[0016]In one embodiment, the invention features a human antibody or antibody fragment comprising a light chain CDR1 selected from the group consisting of SEQ ID NO: 14, 30, 46, 62, 78, 94, 110, 126, 142, 158, 174, 190, 206, 222, 238, 254, 270, 286, 302, 318, 334, 350, 366, 382, 407, 423, 439, 455, 471, 487, 503, 519, 535, 551, 567, 583, 599, 615, 631, 647, 663, 679, 695, 711, 727, 743, 759, 775, 791, 807, 823, 839, 855, 871 and 887, or a substantially identical sequence thereof; a light chain CDR2 selected from the group consisting of SEQ ID NO: 16, 32, 48, 64, 80, 96, 112, 128, 144, 160, 176, 192, 208, 224, 240, 256, 272, 288, 304, 320, 336, 352, 368, 384, 409. 425, 441, 457, 473, 489, 505, 521, 537, 553, 569, 585, 601, 617, 633, 649, 665, 681, 697, 713, 729, 745, 761, 777, 793, 809, 825, 841, 857, 873 and 889, or a substantially identical sequence thereof; and a light chain CDR3 selected from the group consisting of SEQ ID NO: 18, 34, 50, 66, 82, 98, 11, 130, 146, 162, 178, 194, 210, 226, 242, 258, 274, 290, 306, 322, 338, 354, 370, 386, 411, 427, 443, 459, 475, 491, 507, 523, 539, 555, 571, 587, 603, 619, 635, 651, 667, 683, 699, 715, 731, 747, 763, 779, 795, 811, 827, 843, 859, 875 and 891, or a substantially identical sequence thereof. In a preferred embodiment, the antibody or antibody fragment comprises the light chain CDR1, CDR2 and CDR3 selected from the group consisting of SEQ ID NO:439/441/443; 382/384/386; 791/793/795; and 807/809/811.
[0017]In a second aspect, the invention provides nucleic acid molecules encoding the antibodies, or antigen-binding portions, of the invention. Recombinant expression vectors carrying the antibody-encoding nucleic acids of the invention, and host cells into which such vectors have been introduced, are also encompassed by the invention, as are methods of making the antibodies of the invention by culturing the host cells of the invention.
[0018]In one embodiment, the antibody of the invention comprises a HCVR encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO:3, 19, 35, 51, 67, 83, 99, 115, 131, 147, 163, 179, 195, 211, 227, 243, 259, 275, 291, 307, 323, 339, 355, 371, 396, 412, 428, 444, 460, 476, 492, 508, 524, 540, 556, 572, 588, 604, 620, 636, 652, 668, 684, 700, 716, 732, 748, 764, 780, 796, 812, 892, 896, 900, 904, 908, 912, 916, 920, 924, 934, 938, 942, and 946 or a substantially similar sequence having at least 95% homology thereof.
[0019]In one embodiment, the antibody of the invention comprises a LCVR encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO:11, 27, 43, 59, 75, 91, 107, 123, 139, 155, 171, 187, 203, 219, 235, 251, 267, 283, 299, 315, 331, 347, 363, 379, 404, 420, 436, 452, 468, 484, 500, 516, 532, 548, 564, 580, 596, 612, 628, 644, 660, 676, 692, 708, 724, 740, 756, 772, 788, 804, 820, 894, 898, 902, 906, 910, 914, 918, 922, 926, 936, 940, 944, and 948 or a substantially similar sequence having at least 95% homology thereof.
[0020]In one embodiment, the antibody of the invention comprises a HCVR encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO: 3, 19, 35, 51, 67, 83, 99, 115, 131, 147, 163, 179, 195, 211, 227, 243, 259, 275, 291, 307, 323, 339, 355, 371, 396, 412, 428, 444, 460, 476, 492, 508, 524, 540, 556, 572, 588, 604, 620, 636, 652, 668, 684, 700, 716, 732, 748, 764, 780, 796, 812, 892, 896, 900, 904, 908, 912, 916, 920, 924, 934, 938, 942, and 946 or a substantially similar sequence having at least 95% homology thereof, and a LCVR encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO: 11, 27, 43, 59, 75, 91, 107, 123, 139, 155, 171, 187, 203, 219, 235, 251, 267, 283, 299, 315, 331, 347, 363, 379, 404, 420, 436, 452, 468, 484, 500, 516, 532, 548, 564, 580, 596, 612, 628, 644, 660, 676, 692, 708, 724, 740, 756, 772, 788, 804, 820, 894, 898, 902, 906, 910, 914, 918, 922, 926, 936, 940, 944, and 948 or a substantially similar sequence having at least 95% homology thereof.
[0021]In one embodiment, the invention features a human antibody or antibody fragment comprising a heavy chain CDR1 encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO:5, 21, 37, 53, 69, 85, 101, 117, 133, 149, 165, 181, 197, 213, 229, 245, 261, 277, 293, 309, 325, 341, 357, 373, 398, 414, 430, 446, 462, 478, 494, 510, 526, 542, 558, 574, 590, 606, 622, 638, 654, 670, 686, 702, 718, 734, 750, 766, 782, 798, 814, 830, 846, 862 and 878, or a substantially similar sequence having at least 95% homology thereof.
[0022]In one embodiment, the invention features a human antibody or antibody fragment comprising a heavy chain CDR2 encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO:7, 23, 39, 55, 71, 87, 103, 119, 135, 151, 167, 183, 100, 215, 231, 247, 263, 279, 295, 311, 327, 343, 359, 375, 400, 416, 432, 448, 464, 480, 496, 512, 528, 544, 560, 576, 592, 608, 624, 640, 656, 672, 688, 704, 720, 736, 752, 768, 784, 800, 816, 832, 848, 864 and 880, or a substantially similar sequence having at least 95% homology thereof.
[0023]In one embodiment, the invention features a human antibody or antibody fragment comprising a heavy chain CDR3 encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO:9, 25, 41, 57, 73, 89, 105, 121, 137, 153, 169, 185, 201, 217, 233, 249, 265, 281, 297, 313, 329, 345, 361, 377, 402, 418, 434, 450, 466, 482, 498, 514, 530, 546, 562, 578, 594, 610, 626, 642, 658, 674, 690, 706, 722, 738, 754, 770, 786, 802, 818, 834, 850, 866 and 882, or a substantially similar sequence having at least 95% homology thereof.
[0024]In one embodiment, the invention features a human antibody or antibody fragment comprising a heavy chain CDR1 encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO:5, 21, 37, 53, 69, 85, 101, 117, 133, 149, 165, 181, 197, 213, 229, 245, 261, 277, 293, 309, 325, 341, 357, 373, 398, 414, 430, 446, 462, 478, 494, 510, 526, 542, 558, 574, 590, 606, 622, 638, 654, 670, 686, 702, 718, 734, 750, 766, 782, 798, 814, 830, 846, 862 and 878, or a substantially similar sequence having at least 95% homology thereof; a heavy chain CDR2 encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO:7, 23, 39, 55, 71, 87, 103, 119, 135, 151, 167, 183, 100, 215, 231, 247, 263, 279, 295, 311, 327, 343, 359, 375, 400, 416, 432, 448, 464, 480, 496, 512, 528, 544, 560, 576, 592, 608, 624, 640, 656, 672, 688, 704, 720, 736, 752, 768, 784, 800, 816, 832, 848, 864 and 880, or a substantially similar sequence having at least 95% homology thereof; and a heavy chain CDR3 encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO: 9, 25, 41, 57, 73, 89, 105, 121, 137, 153, 169, 185, 201, 217, 233, 249, 265, 281, 297, 313, 329, 345, 361, 377, 402, 418, 434, 450, 466, 482, 498, 514, 530, 546, 562, 578, 594, 610, 626, 642, 658, 674, 690, 706, 722, 738, 754, 770, 786, 802, 818, 834, 850, 866 and 882, or a substantially similar sequence having at least 95% homology thereof. In a preferred embodiment, the antibody or antibody fragment comprises heavy chain CDR1, CDR2 and CDR3 encoded b a nucleic acid sequence selected from the group consisting of SEQ ID NO:430/432/434; 373/375/377; 782/784/786; and 798/800/802.
[0025]In one embodiment, the invention features a human antibody or antibody fragment comprising a light chain CDR1 encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO:13, 29, 45, 61, 77, 93, 109, 125, 141, 157, 173, 189, 205, 221, 237, 253, 269, 285, 301, 317, 333, 349, 365, 381, 406, 422, 438, 454, 470, 486, 502, 518, 534, 550, 566, 582, 598, 614, 630, 646, 662, 678, 694, 710, 726, 742, 758, 774, 790, 806, 822, 838, 854, 870 and 886, or a substantially similar sequence having at least 95% homology thereof.
[0026]In one embodiment, the invention features a human antibody or antibody fragment comprising a light chain CDR2 encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO:15, 31, 47, 63, 79, 95, 111, 127, 143, 159, 175, 191, 207, 223, 239, 255, 271, 287, 303, 319, 335, 351, 367, 383, 408, 424, 440, 456, 472, 488, 504, 520, 536, 552, 568, 584, 600, 616, 632, 648, 664, 680, 696, 712, 728, 744, 760, 776, 792, 808, 824, 840, 856, 872, and 888, or a substantially similar sequence having at least 95% homology thereof.
[0027]In one embodiment, the invention features a human antibody or antibody fragment comprising a light chain CDR3 encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO:17, 33, 49, 65, 81, 97, 113, 129, 145, 161, 177, 193, 209, 225, 241, 257, 273, 289, 305, 321, 337, 353, 369, 385, 410, 426, 442, 458, 474, 490, 506, 522, 538, 554, 570, 586, 602, 618, 634, 650, 666, 682, 698, 714, 730, 746, 762, 778, 794, 810, 826, 842, 858, 874 and 890, or a substantially similar sequence having at least 95% homology thereof.
[0028]In one embodiment, the invention features a human antibody or antibody fragment comprising a light chain CDR1 encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO:13, 29, 45, 61, 77, 93, 109, 125, 141, 157, 173, 189, 205, 221, 237, 253, 269, 285, 301, 317, 333, 349, 365, 381, 406, 422, 438, 454, 470, 486, 502, 518, 534, 550, 566, 582, 598, 614, 630, 646, 662, 678, 694, 710, 726, 742, 758, 774, 790, 806, 822, 835, 851, 867 and 883, or a substantially similar sequence having at least 95% homology thereof; a light chain CDR2 encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO: 15, 31, 47, 63, 79, 95, 111, 127, 143, 159, 175, 191, 207, 223, 239, 255, 271, 287, 303, 319, 335, 351, 367, 383, 408, 424, 440, 456, 472, 488, 504, 520, 536, 552, 568, 584, 600, 616, 632, 648, 664, 680, 696, 712, 728, 744, 760, 776, 792, 808, 824, 840, 856, 872, and 888, or a substantially similar sequence having at least 95% homology thereof; and a light chain CDR3 encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO: 17, 33, 49, 65, 81, 97, 113, 129, 145, 161, 177, 193, 209, 225, 241, 257, 273, 289, 305, 321, 337, 353, 369, 385, 410, 426, 442, 458, 474, 490, 506, 522, 538, 554, 570, 586, 602, 618, 634, 650, 666, 682, 698, 714, 730, 746, 762, 778, 794, 810, 826, 842, 858, 874 and 890, or a substantially similar sequence having at least 95% homology thereof. In a preferred embodiment, the antibody or antibody fragment comprises the light chain CDR1, CDR2 and CDR3 encoded by a nucleic acid sequence selected from the group consisting of SEQ ID NO:438/440/442; 381/383/385; 790/792/794; and 806/808/810.
[0029]In a third aspect, the invention features an isolated antibody or antibody fragment that specifically binds hDll4, comprising a CDR 1, 2 and 3 selected from the group consisting of (a) a heavy chain CDR1 region comprising an amino acid sequence of the formula X1-X2-X3-X4-X5-X6-X7-X8 (SEQ ID NO:928), wherein X1 is Gly; X2 is Phe or Tyr; X3 is Thr; X4 is Phe; X5 is Ser, Thr or Asn; X6 is Ser, Asn or Tyr; X7 is Tyr or Phe; and X8 is Gly or Ala; (b) a heavy chain CDR2 region comprising an amino acid sequence of the formula X1-X2-X3-X4-X5-X6-X7-X8 (SEQ ID NO:929), wherein X1 is Ile or Leu; X2 is Trp or Ser; X3 is Tyr, Ala or Gly; X4 is Asp, Ser or Tyr; X5 is Gly or Asp; X6 is Ser, Gly, Thr or Val; X7 is Asn or Asp; and X8 is Lys or Arg; (c) a heavy chain CDR3 region comprising an amino acid sequence of the formula X1-X2-X3-X4-X5-X6-X7-X8-X9-X- 10-X11-X12-X13-X14-X15-X16 (SEQ ID NO:930), wherein X1 is Ala or Ser; X2 is Arg or Lys; X3 is Asp or Tyr; X4 is Ser, Gly or His; X5 is Asp, Ala or Trp; X6 is Asn, or Phe; X7 is Tyr, Arg or Lys; X8 is His or Ser; X9 is Gly or Trp; X10 is Tyr or Phe; X11 is Glu or Asp; X12 is Gly, His or Pro; X13 is Tyr, Trp or absent; X14 is Phe or absent; X15 is Asp or absent; and X16 is Pro or absent.
[0030]In a preferred embodiment, the antibody or antibody fragment comprises heavy chain CDR 1, 2 and 3 selected from the group consisting of (a) a heavy chain CDR1 region comprising an amino acid sequence of the formula X1-X2-X3-X4-X5-X6-X7-X8 (SEQ ID NO:928), wherein X1 is Gly; X2 is Phe; X3 is Thr; X4 is Phe; X5 is Ser or Asn; X6 is Ser or Asn; X7 is Tyr or Phe; and X8 is Gly or Ala; (b) a heavy chain CDR2 region comprising an amino acid sequence of the formula X1-X2-X3-X4-X5-X6-X7-X8 (SEQ ID NO:929), wherein X1 is Ile or Leu; X2 is Trp or Ser; X3 is Tyr or Gly; X4 is Asp or Ser; X5 is Gly; X6 is Ser, Thr or Val; X7 is Asn or Asp; and X8 is Lys or Arg; (c) a heavy chain CDR3 region comprising an amino acid sequence of the formula X1-X2-X3-X4-X5-X6-X7-X8-X9-X- 10-X11-X12-X13-X14-X15-X16 (SEQ ID NO:930), wherein X1 is Ala or Ser; X2 is Arg or Lys; X3 is Asp; X4 is Gly or His; X5 is Asp or Ala; X6 is Phe; X7 is Tyr or Arg; X8 is Ser; X9 is Gly; X10 is Tyr; X11 is Glu; X12 is Gly or His; X13 is Tyr or Trp; X14 is Phe or absent; X15 is Asp or absent; and X16 is Pro or absent.
[0031]In a further embodiment, the isolated antibody or antibody fragment further comprises (d) a light chain CDR1 region comprising an amino acid sequence of the formula X1-X2-X3-X4-X5-X6-X7 (SEQ ID NO:931), wherein X1 is Gln; X2 is Ser; X3 is Val; X4 is Arg, Ser or Thr; X5 is Ser or Gly; X6 is Ser or Tyr; and X7 is Tyr or absent; (e) a light chain CDR2 region comprising an amino acid sequence of the formula X1-X2-X3 (SEQ ID NO:932), wherein X1 is Gly or Asp; X2 is Ala or Thr; and X3 is Ser; and (f) a light chain CDR3 region comprising an amino acid sequence of the formula X1-X2-X3-X4-X5-X6-X7-X8-X- 9 (SEQ ID NO:933), wherein X1 is Gln; X2 is Gln or His; X3 is Tyr, Arg or Ser; X4 is Gly, Ser or Ala; X5 is Ser, Asn or Phe; X6 is Trp or Ser; X7 is Pro; X8 is Trp, Pro or Arg; and X9 is Thr.
[0032]In a preferred embodiment, the isolated antibody or antibody fragment further comprises (d) a light chain CDR1 region comprising an amino acid sequence of the formula X1-X2-X3-X4-X5-X6-X7 (SEQ ID NO:931), wherein X1 is Gln; X2 is Ser; X3 is Val; X4 is Arg or Ser; X5 is Ser; X6 is Ser or Tyr; and X7 is Tyr or absent; (e) a light chain CDR2 region comprising an amino acid sequence of the formula X1-X2-X3 (SEQ ID NO:932), wherein X1 is Gly or Asp; X2 is Ala or Thr; and X3 is Ser; and (f) a light chain CDR3 region comprising an amino acid sequence of the formula X1-X2-X3-X4-X5-X6-X7-X8-X9 (SEQ ID NO:933), wherein X1 is Gln; X2 is Gln or His; X3 is Tyr or Arg; X4 is Gly or Ser; X5 is Ser or Asn; X6 is Trp or Ser; X7 is Pro; X8 is Pro or Arg; and X9 is Thr.
[0033]In a fourth aspect, the invention features a fully human antibody or antibody fragment which binds hDll4 with an IC50 of less than about 10 nM, as measured in in vitro assay or ELISA-based Dll4 blocking assay (described below). In a preferred embodiment, the antibody of the invention exhibits an IC50 of about 500 pM or less. In an even more preferred embodiment, the antibody of the invention exhibits an IC50 of about 100 pM or less.
[0034]In one embodiment, the invention provides a fully human monoclonal antibody which specifically binds and inhibits human Dll4 and exhibits an IC50 of less than or equal to about 150 pM, 100 pM, 75 pM, or 50 pM, as measured by Notch-inducible luciferase bioassay with hDll4-Fc. As shown in the experimental section below, the anti-hDll4 antibodies of the invention do not cross-react with closely related delta proteins, such as hDll1 and hDll3.
[0035]In one embodiment, the invention provides an isolated human antibody, or an antigen-binding portion thereof, that binds hDll4 with a KD of less than about 500 pM, preferably less than about 300 pM, even more preferably less than about 100 pM, less than about 50 pM, less than about 10 pM, as determined by surface plasmon resonance (BIACORE®), for example, using dimeric hDll4 (Table 2).
[0036]The invention encompasses anti-hDll4 antibodies having a modified glycosylation pattern. In some applications, modification to remove undesirable glycosylation sites may be useful, or an antibody lacking a fucose moiety present on the oligosaccharide chain, for example, to increase antibody dependent cellular cytotoxicity (ADCC) function (see Shield et al. (2002) JBC 277:26733). In other applications, modification of a galactosylation can be made in order to modify complement dependent cytotoxicity (CDC).
[0037]The invention includes anti-hDll4 antibodies which bind specific epitopes of hDll4 and are capable of blocking the biological activity of hDll4. The extracellular domain of Dll4 is composed of an N-terminal domain, a Delta/Serrate/Lag-2 (DSL) domain, and a tandem of eight epidermal growth factor (EGF)-like repeats. Generally, the EGF domains are recognized as occurring at about amino acid residues 218-251 (domain 1), 252-282 (domain 2), 284-322 (domain 3), 324-360 (domain 4), and 362-400 (domain 5), with the DSL domain at about amino acid residues 173-217 and the N-terminal domain at about amino acid residues 27-172 of hDll4 (SEQ ID NO:2).
[0038]In one embodiment, a blocking antibody of the invention binds within amino acids residues 27 to 524 of SEQ ID NO:2. In a more specific embodiment, a blocking antibody of the invention binds an epitope within the N-terminus-DSL domains 27-217 of SEQ ID NO:2; in an even more specific embodiment, the blocking antibody binds an epitope within about amino acid residues 27-172 (N-terminal domain) or 173-217 (DSL domain). In another embodiment, a blocking antibody of the invention binds the EGF-2 epitope within about amino acids residues 252-282 of SEQ ID NO:2.
[0039]In a fifth aspect, the invention features a composition comprising a recombinant human anti-human Dll4 antibody and an acceptable carrier. Further included in the invention are vectors and host cells comprising vectors which contain nucleic acid molecules encoding the human anti-hDll4 antibody of the invention, as well as methods of producing these novel antibodies, comprising growing a host cell comprising nucleic acid encoding the anti-hDll4 antibody of the invention or an antibody fragment, under conditions permitting production of the protein and recovering the protein so produced.
[0040]In a sixth aspect, the invention features methods for inhibiting hDll4 activity using an antibody, or antigen-binding portion thereof, of the invention. In one embodiment, the method comprises contacting hDll4 with the instant antibody or antigen-binding portion thereof, such that hDll4 is inhibited from binding to Notch receptor, for example Notch-1. In another embodiment, the method comprises administering an antibody or antibody fragment of the invention, to a human subject suffering from a disorder which is ameliorated by inhibition of Dll4 activity. The disorder treated is a disease or condition which is improved, ameliorated, inhibited or prevented by removal, inhibition or reduction of Dll4 activity, for example, pathological vascularization associated with tumor angiogenesis and cancer, immunodeficiency diseases, transplant rejection, or inflammation; and neurodegenerative conditions, e.g., associated with prion disease.
[0041]Other objects and advantages will become apparent from a review of the ensuing detailed description.
DETAILED DESCRIPTION
[0042]Before the present methods are described, it is to be understood that this invention is not limited to particular methods, and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
[0043]As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus for example, a reference to "a method" includes one or more methods, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure.
[0044]Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference in their entirety.
DEFINITIONS
[0045]"Delta-like ligand 4", "Dll4", "hDll4" are used interchangeably to refer to the protein encoded by the nucleic acid sequence of SEQ ID NO:1 and the protein having the amino acid sequence of SEQ ID NO:2.
[0046]The term "antibody", as used herein, is intended to refer to immunoglobulin molecules comprised of four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region is comprised of three domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementary determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
[0047]The term "high affinity" antibody refers to those antibodies having a binding affinity to hDll4 of at least 10-8 M; preferably 10-9 M; even more preferably 10-10 M, as measured by surface plasmon resonance, e.g., BIACORE® or solution-affinity ELISA.
[0048]By the term "slow off rate" or "Koff" is meant an antibody that dissociates from hDll4 with a rate constant of 1×10-3 s-1 or less, preferably 1×10-4 s-1 or less, as determined by surface plasmon resonance, e.g., BIACORE®.
[0049]A "neutralizing" or "blocking" antibody, is intended to refer to an antibody whose binding to Dll4 results in inhibition of the biological activity of Dll4. This inhibition of the biological activity of Dll4 can be assessed by measuring one or more indicators of Dll4 biological activity. These indicators of Dll4 biological activity can be assessed by one or more of several standard in vitro or in vivo assays known in the art (see examples below). Preferably, the ability of an antibody to neutralize Dll4 activity is assessed by inhibition of Dll4 binding to a Notch receptor.
[0050]The term "antigen-binding portion" of an antibody (or simply "antibody portion" or "antibody fragment"), as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., hDll4). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments encompassed within the term "antigen-binding portion" of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al. (1989) Nature 241:544-546), which consists of a VH domain; and (vi) an isolated CDR. Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). Such single chain antibodies are also intended to be encompassed within the term "antigen-binding portion" of an antibody. Other forms of single chain antibodies, such as diabodies are also encompassed. Diabodies are bivalent, bispecific antibodies in which VH and VL domains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen binding sites (see e.g., Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak et al. (1994) Structure 2:1121-1123).
[0051]Still further, an antibody or antigen-binding portion thereof may be part of a larger immunoadhesion molecule, formed by covalent or noncovalent association of the antibody or antibody portion with one or more other proteins or peptides. Examples of such immunoadhesion molecules include use of the streptavidin core region to make a tetrameric scFv molecule (Kipriyanov et al. (1995) Human Antibodies and Hybridomas 6:93-101) and use of a cysteine residue, a marker peptide and a C-terminal polyhistidine tag to make bivalent and biotinylated scFv molecules (Kipriyanov et al. (1994) Mol. Immunol. 31:1047-1058). Antibody portions, such as Fab and F(ab')2 fragments, can be prepared from whole antibodies using conventional techniques, such as papain or pepsin digestion, respectively, of whole antibodies. Moreover, antibodies, antibody portions and immunoadhesion molecules can be obtained using standard recombinant DNA techniques, as described herein.
[0052]The term "human antibody", as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDR3. However, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
[0053]The term "recombinant human antibody", as used herein, is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295) or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.
[0054]An "isolated antibody", as used herein, is intended to refer to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds hDll4 is substantially free of antibodies that specifically bind antigens other than hDll4). An isolated antibody that specifically binds hDll4 may, however, have cross-reactivity to other antigens, such as hDll4 molecules from other species. Moreover, an isolated antibody may be substantially free of other cellular material and/or chemicals.
[0055]The term "surface plasmon resonance", as used herein, refers to an optical phenomenon that allows for the analysis of real-time biospecific interactions by detection of alterations in protein concentrations within a biosensor matrix, for example using the BIACORE® system (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.).
[0056]The term "KD", as used herein, is intended to refer to the dissociation constant of a particular antibody-antigen interaction.
[0057]The term "epitope" includes any determinant, preferably a polypeptide determinant, capable of specific binding to an immunoglobulin or T-cell receptor. In certain embodiments, epitope determinants include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups, and, in certain embodiments, may have specific three-dimensional structural characteristics, and/or specific charge characteristics. An epitope is a region of an antigen that is bound by an antibody. In certain embodiments, an antibody is said to specifically bind an antigen when it preferentially recognizes its target antigen in a complex mixture of proteins and/or macromolecules. In preferred embodiments, an antibody is said to specifically bind an antigen when the equilibrium dissociation constant is less than or equal to 10-8 M, more preferably when the equilibrium dissociation constant is less than or equal to 10-9 M, and most preferably when the dissociation constant is less than or equal to 10-10 M.
[0058]A protein or polypeptide is "substantially pure," "substantially homogeneous" or "substantially purified" when at least about 60 to 75% of a sample exhibits a single species of polypeptide. The polypeptide or protein may be monomeric or multimeric. A substantially pure polypeptide or protein will typically comprise about 50%, 60, 70%, 80% or 90% W/W of a protein sample, more usually about 95%, and preferably will be over 99% pure. Protein purity or homogeneity may be indicated by a number of means well known in the art, such as polyacrylamide gel electrophoresis of a protein sample, followed by visualizing a single polypeptide band upon staining the gel with a stain well known in the art. For certain purposes, higher resolution may be provided by using HPLC or other means well known in the art for purification.
[0059]The term "polypeptide analog or variant" as used herein refers to a polypeptide that is comprised of a segment of at least 25 amino acids that has substantial identity to a portion of an amino acid sequence and that has at least one of the following properties: (1) specific binding to hDll4 under suitable binding conditions, or (2) ability to block Dll4 binding to a Notch receptor. Typically, polypeptide analogs or variants comprise a conservative amino acid substitution (or insertion or deletion) with respect to the naturally-occurring sequence. Analogs typically are at least 20 amino acids long, preferably at least 50, 60, 70, 80, 90, 100, 150 or 200 amino acids long or longer, and can often be as long as a full-length naturally-occurring polypeptide.
[0060]Preferred amino acid substitutions are those which: (1) reduce susceptibility to proteolysis, (2) reduce susceptibility to oxidation, (3) alter binding affinity for forming protein complexes, (4) alter binding affinities, and (4) confer or modify other physicochemical or functional properties of such analogs. Analogs can include various mutations of a sequence other than the naturally-occurring peptide sequence. For example, single or multiple amino acid substitutions (preferably conservative amino acid substitutions) may be made in the naturally-occurring sequence (preferably in the portion of the polypeptide outside the domain(s) forming intermolecular contacts. A conservative amino acid substitution should not substantially change the structural characteristics of the parent sequence (e.g., a replacement amino acid should not tend to break a helix that occurs in the parent sequence, or disrupt other types of secondary structure that characterizes the parent sequence). Examples of art-recognized polypeptide secondary and tertiary structures are described in Proteins, Structures and Molecular Principles (Creighton 1984 W. H. Freeman and Company, New York; Introduction to Protein Structure (Branden & Tooze, eds., 1991, Garland Publishing, NY); and Thornton et al. 1991 Nature 354:105, which are each incorporated herein by reference.
[0061]Non-peptide analogs are commonly used in the pharmaceutical industry as drugs with properties analogous to those of the template peptide. These types of non-peptide compound are termed "peptide mimetics" or "peptidomimetics" (see, for example, Fauchere (1986) J. Adv. Drug Res. 15:29; and Evans et al. (1987) J. Med. Chem. 30:1229, which are incorporated herein by reference. Systematic substitution of one or more amino acids of a consensus sequence with a D-amino acid of the same type (e.g., D-lysine in place of L-lysine) may also be used to generate more stable peptides. In addition, constrained peptides comprising a consensus sequence or a substantially identical consensus sequence variation may be generated by methods known in the art (Rizo et al. (1992) Ann. Rev. Biochem. 61:387, incorporated herein by reference), for example, by adding internal cysteine residues capable of forming intramolecular disulfide bridges which cyclize the peptide.
[0062]The term "percent sequence identity" in the context of nucleic acid sequences refers to the residues in two sequences which are the same when aligned for maximum correspondence. The length of sequence identity comparison may be over a stretch of at least about nine nucleotides or more, usually at least about 18 nucleotides, more usually at least about 24 nucleotides, typically at least about 28 nucleotides, more typically at least about 32 nucleotides, and preferably at least about 36, 48 or more nucleotides. There are a number of different algorithms known in the art which can be used to measure nucleotide sequence identity. For instance, polynucleotide sequences can be compared using FASTA, Gap or Bestfit, which are programs in Wisconsin Package Version 10.0, Genetics Computer Group (GCG), Madison, Wis. FASTA, which includes, e.g., the programs FASTA2 and FASTA3, provides alignments and percent sequence identity of the regions of the best overlap between the query and search sequences (Pearson (1990) Methods Enzymol. 183:63-98 and (2000) Methods Mol. Biol. 132:185-219, each herein incorporated by reference). Unless otherwise specified, default parameters for a particular program or algorithm are used. For instance, percent sequence identity between nucleic acid sequences can be determined using FASTA with its default parameters (a word size of 6 and the NOPAM factor for the scoring matrix) or using Gap with its default parameters as provided in GCG Version 6.1, herein incorporated by reference.
[0063]A reference to a nucleic acid sequence encompasses its complement unless otherwise specified. Thus, a reference to a nucleic acid molecule having a particular sequence should be understood to encompass its complementary strand, with its complementary sequence. Generally, the art uses the terms "percent sequence identity", "percent sequence similarity" and "percent sequence homology" interchangeably. In this application, these terms shall have the same meaning with respect to nucleic acid sequences.
[0064]The term "substantial similarity", or "substantial sequence similarity," when referring to a nucleic acid or fragment thereof, indicates that, when optimally aligned with appropriate nucleotide insertions or deletions with another nucleic acid (or its complementary strand), there is nucleotide sequence identity in at least about 90%, preferably at least about 95%, and more preferably at least about 96%, 97%, 98% or 99% of the nucleotide bases, as measured by any well-known algorithm of sequence identity, such as FASTA, BLAST or Gap, as discussed above.
[0065]As applied to polypeptides, the term "substantial identity" or "substantially identical" means that two peptide sequences, when optimally aligned, such as by the programs GAP or BESTFIT using default gap weights, share at least 80% sequence identity, preferably at least 90% or 95% sequence identity, even more preferably at least 98% or 99% sequence identity. Preferably, residue positions which are not identical differ by conservative amino acid substitutions. A "conservative amino acid substitution" is one in which an amino acid residue is substituted by another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity). In general, a conservative amino acid substitution will not substantially change the functional properties of a protein. In cases where two or more amino acid sequences differ from each other by conservative substitutions, the percent sequence identity or degree of similarity may be adjusted upwards to correct for the conservative nature of the substitution. Means for making this adjustment are well-known to those of skill in the art. See, e.g., Pearson (1994) Methods Mol. Biol. 24: 307-331, herein incorporated by reference. Examples of groups of amino acids that have side chains with similar chemical properties include 1) aliphatic side chains: glycine, alanine, valine, leucine and isoleucine; 2) aliphatic-hydroxyl side chains: serine and threonine; 3) amide-containing side chains: asparagine and glutamine; 4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; 5) basic side chains: lysine, arginine, and histidine; and 6) sulfur-containing side chains are cysteine and methionine. Preferred conservative amino acids substitution groups are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamate-aspartate, and asparagine-glutamine. Alternatively, a conservative replacement is any change having a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al. (1992) Science 256: 1443 45, herein incorporated by reference. A "moderately conservative" replacement is any change having a nonnegative value in the PAM250 log-likelihood matrix.
[0066]Sequence similarity for polypeptides, which is also referred to as sequence identity, is typically measured using sequence analysis software. Protein analysis software matches similar sequences using measures of similarity assigned to various substitutions, deletions and other modifications, including conservative amino acid substitutions. For instance, GCG contains programs such as "Gap" and "Bestfit" which can be used with default parameters to determine sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from different species of organisms or between a wild type protein and a mutein thereof. See, e.g., GCG Version 6.1. Polypeptide sequences also can be compared using FASTA using default or recommended parameters, a program in GCG Version 6.1. FASTA (e.g., FASTA2 and FASTA3) provides alignments and percent sequence identity of the regions of the best overlap between the query and search sequences (Pearson (2000) supra). Another preferred algorithm when comparing a sequence of the invention to a database containing a large number of sequences from different organisms is the computer program BLAST, especially blastp or tblastn, using default parameters. See, e.g., Altschul et al. (1990) J. Mol. Biol. 215:403 410 and Altschul et al. (1997) Nucleic Acids Res. 25:3389 402, each of which is herein incorporated by reference.
[0067]The length of polypeptide sequences compared for homology will generally be at least about 16 amino acid residues, usually at least about 20 residues, more usually at least about 24 residues, typically at least about 28 residues, and preferably more than about 35 residues. When searching a database containing sequences from a large number of different organisms, it is preferable to compare amino acid sequences.
Preparation of Human Antibodies
[0068]Methods for generating human antibodies include, for example, VELOCIMMUNE® (Regeneron Pharmaceuticals), XENOMOUSE® technology (Abgenix), the "minilocus" approach, and phage display. The VELOCIMMUNE® technology (U.S. Pat. No. 6,596,541) encompasses a method of generating a high specificity fully human antibody to a select antigen. This technology involves generation of a transgenic mouse having a genome comprising human heavy and light chain variable regions operably linked to endogenous mouse constant region loci such that the mouse produces an antibody comprising a human variable region and a mouse constant region in response to antigenic stimulation. The DNA encoding the variable regions of the heavy and light chains of the antibody are isolated and operably linked to DNA encoding the human heavy and light chain constant regions. The DNA is then expressed in a cell capable of expressing the fully human antibody. In specific embodiment, the cell is a CHO cell.
[0069]The XENOMOUSE® technology (Green et al. (1994) Nature Genetics 7:13-21) generates a mouse having both human variable and constant regions from both the heavy chain and kappa light chain loci. In an alternative approach, others have utilized a "minilocus" approach in which an exogenous Ig locus is mimicked through inclusion of individual genes from the Ig locus (see, for example, U.S. Pat. No. 5,545,807). The DNA encoding the variable regions can be isolated with or without being operably linked to the DNA encoding the human heavy and light chain constant region.
[0070]Other methods of generating human antibodies, including isolation from a human donor, are known. See, for example, U.S. Pat. No. 6,787,637, herein specifically incorporated by reference in its entirety.
[0071]Antibodies may be therapeutically useful in blocking a ligand-receptor interaction or inhibiting receptor component interaction, rather than by killing cells through fixation of complement and participation in CDC. The constant region of an antibody is important in the ability of an antibody to fix complement and participate in CDC or direct cell killing through antibody-dependent cellular cytoxicity (ADCC). Thus, the isotype of an antibody may be selected on the basis of the desirability for the antibody to fix complement.
[0072]Human immunoglobulins can exist in two forms that are associated with hinge heterogeneity. In one form, an immunoglobulin molecule comprises a stable four chain construct of approximately 150-160 kDa in which the dimers are held together by an interchain heavy chain disulfide bond. In a second form, the dimers are not linked via inter-heavy chain disulfide bonds and a molecule of about 75-80 kDa is formed composed of a single light and heavy chain. These forms have been difficult to separate, even after affinity purification.
[0073]The frequency of appearance of the second form in various intact IgG isotypes is due to, but not limited to, structural differences associated with the hinge region isotype of the antibody. In fact, a single amino acid substitution in the hinge region of the human IgG4 hinge can significantly reduce the appearance of the second form (Angal et al. 1993 Molecular Immunology 30:105) to levels typically observed using a human IgG1 hinge. The instant invention encompasses antibodies having one or more mutations in the hinge, CH2 or CH3 region which may be desirable, for example, in production to improve the yield, or modulate effector functions.
[0074]Antibodies of the invention are preferably prepared with the use of VELOCIMMUNE® technology. A transgenic mouse in which the endogenous immunoglobulin heavy and light chain variable regions are replaced with the corresponding human variable regions is challenged with the antigen of interest, and lymphatic cells (such as B-cells) recovered from the mice that express antibodies. The lymphatic cells may be fused with a myeloid-type cell line to prepare immortal hybridoma cell lines, and such hybridoma cell lines are screened and selected to identify hybridoma cell lines that produce antibodies specific to the antigen of interest. DNA encoding the variable regions of the heavy chain and light chain may be isolated and linked to desirable isotypic constant regions of the heavy chain and light chain. Such an antibody protein may be produced in a cell, such as a CHO cell. Alternatively, DNA encoding the antigen-specific chimeric antibodies may be isolated directly from antigen-specific lymphocytes. In various embodiments, the transgenic mouse comprises 12 functional human variable heavy chain genes and 11 functional human variable kappa light chain genes; 25 to 30 human variable heavy chain genes and from 18 to 20 human variable kappa light chain genes; 43 to 48 human variable heavy chain genes and 20 to 22 human variable kappa light chain genes; or about 80 human variable heavy chain genes and about 40 human variable kappa light chain genes.
[0075]In general, the antibodies of the instant invention possess very high affinities, typically possessing KD of from about 10-9 through about 10-11 M, when measured by binding to antigen either immobilized on solid phase or in solution phase. The mouse constant regions are replaced with desired human constant regions to generate the fully human antibodies of the invention, for example wild-type or modified IgG1 or IgG4 (for example, SEQ ID NO:950, 951, or 952). While the constant region selected may vary according to specific use, high affinity antigen-binding and target specificity characteristics reside in the variable region.
[0076]Cancer, infectious diseases, autoimmunity, immunodeficiency, transplants, inflammation, injury and degenerative conditions can be treated by modulation of the immune system. In cases of disease due to inappropriate function or hyperactivity of the immune system, such as autoimmunity or inflammation, can be ameliorated through inhibition of immune cell function or reduction of immune cell numbers. This can be accomplished by blockade of positive signals or stimulation of negative signals on immune cell populations critical to the disease process, such as T, B or NK cells, neutrophils, macrophages, antigen presenting cells, mast cells or other cell types. Overactivity can also be inhibited through elimination of various immune cell populations by stimulation of apoptosis, targeting of specific surface receptors with depleting antibodies or antibody-drug conjugates, or the blockade or alteration of the differentiation of immune cell lineages or specific cell types. Inefficient or reduced immune function can cause or exacerbate disorders such as cancer, infectious disease, and other immunodeficiencies. Hypoactivity of the immune system can be improved through activation of immune cells by stimulation of positive signals by crosslinking or agonistic antibodies or blockade of negative signals. Immune cell populations can be increased by stimulation of development of some or all immune cell lineages, prevention of apoptosis, or elimination of inhibitory signals. In a specific application, the antibodies of the invention are useful for treatment, inhibition or amelioration of a condition or disease such as, for example, cancer, immunodeficiency, transplant rejection, or inflammation.
Epitope Mapping and Related Technologies
[0077]To screen for antibodies which bind to a particular epitope (e.g., those which block binding of IgE to its high affinity receptor), a routine cross-blocking assay such as that described in Harlow and Lane (1990) supra can be performed. Other methods include alanine scanning mutants, peptide blots (Reineke (2004) Methods Mol Biol 248:443-63) (herein specifically incorporated by reference in its entirety), or peptide cleavage analysis. In addition, methods such as epitope excision, epitope extraction and chemical modification of antigens can be employed (Tomer (2000) Protein Science 9: 487-496) (herein specifically incorporated by reference in its entirety).
[0078]The term "epitope" refers to a site on an antigen to which B and/or T cells respond. B-cell epitopes can be formed both from contiguous amino acids or noncontiguous amino acids juxtaposed by tertiary folding of a protein. Epitopes formed from contiguous amino acids are typically retained on exposure to denaturing solvents, whereas epitopes formed by tertiary folding are typically lost on treatment with denaturing solvents. An epitope typically includes at least 3, and more usually, at least 5 or 8-10 amino acids in a unique spatial conformation.
[0079]Modification-Assisted Profiling (MAP), also known as Antigen Structure-based Antibody Profiling (ASAP) is a method that categorizes large numbers of monoclonal antibodies (mAbs) directed against the same antigen according to the similarities of the binding profile of each antibody to chemically or enzymatically modified antigen surfaces (U.S. patent Publication No. 2004/0101920, herein specifically incorporated by reference in its entirety). Each category may reflect a unique epitope either distinctly different from or partially overlapping with epitope represented by another category. This technology allows rapid filtering of genetically identical antibodies, such that characterization can be focused on genetically distinct antibodies. When applied to hybridoma screening, MAP may facilitate identification of rare hybridoma clones that produce mAbs having the desired characteristics. MAP may be used to sort the hDll4 antibodies of the invention into groups of antibodies binding different epitopes.
[0080]Agents useful for altering the structure of the immobilized antigen are enzymes, such as, for example proteolytic enzymes, for example, trypsin, endoproteinase Glu-C, endoproteinase Asp-N, chymotrypsin, etc. Agents useful for altering the structure of the immobilized antigen may also be chemical agents, such as, succinimidyl esters and their derivatives, primary amine-containing compounds, hydrazines and carbohydrazines, free amino acids, etc.
[0081]The antigen protein may be immobilized on either biosensor chip surfaces or polystyrene beads. The latter can be processed with, for example, an assay such as multiplex LUMINEX® detection assay (Luminex Corp., Austin, Tex.). Because of the capacity of LUMINEX® to handle multiplex analysis with up to 100 different types of beads, LUMINEX® provides almost unlimited antigen surfaces with various modifications, resulting in improved resolution in antibody epitope profiling over a biosensor assay.
Therapeutic Administration and Formulations
[0082]The administration of therapeutic entities in accordance with the invention will be administered with suitable carriers, excipients, and other agents that are incorporated into formulations to provide improved transfer, delivery, tolerance, and the like. A multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences (15th ed, Mack Publishing Company, Easton, Pa.). These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LIPOFECTIN®), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. Any of the foregoing mixtures may be appropriate in treatments and therapies in accordance with the present invention, provided that the active ingredient in the formulation is not inactivated by the formulation and the formulation is physiologically compatible and tolerable with the route of administration. See also Powell et al. "Compendium of excipients for parenteral formulations" PDA (1998) J Pharm Sci Technol. 52:238-311 and the citations therein for additional information related to excipients and carriers well known to pharmaceutical chemists.
EXAMPLES
Example 1
Generation of Human Antibodies to Human Dll4
[0083]Mice may be immunized by any method known in the art (see, for example, Harlow and Lane supra). In one embodiment, hDll4 antigen is administered directly to VELOCIMMUNE® mice comprising DNA loci encoding human Ig heavy chain variable regions and kappa light chain variable regions, with an adjuvant to stimulate the immune response. Such an adjuvant includes complete and incomplete Freund's adjuvant, MPL+TDM adjuvant system (Sigma), or RIBI (muramyl dipeptides) (see O'Hagan 2000 Vaccine Adjuvant, by Human Press, Totawa, N.J.). The antibody immune response is monitored by standard antigen specific immunoassay. When a desired immune response is achieved, antibody-expressing B cells were harvested and fused with mouse myeloma cells to preserve their viability, forming hybridoma cell lines. Such hybridoma cell lines are screened and selected to identify cell lines that produce antigen-specific antibodies using assays as described below.
[0084]Alternatively, antigen-specific hybridoma cells may be isolated by flow cytometry. Briefly, after fusion to myeloma cells, pooled hybridoma cells were grown for 10 days in HAT medium. The cells were then harvested and stained with biotin-labeled Dll4 at 2 mg/ml for one hour, followed by addition of phycoerythrin-streptavidin. The fluorescence-labeled cells were sorted by flow cytometry (single cell per well into 96 well plates containing hybridoma growth medium), cultured for 8-10 days, and conditioned media screened for the presence of functionally desirable monoclonal antibodies, as described below.
[0085]Anti-hDll4 antibodies generated via direct isolation of splenocytes. Antigen-specific antibodies may also be isolated directly from antigen-immunized B cells without fusion to myeloma cells, as described in U.S. Patent Publication 2007/0280945A1, herein specifically incorporated by reference in its entirety. Stable recombinant antibody-expressing CHO cell lines were established from the isolated proper recombinants.
Example 2
Antigen Binding Affinity Determination
[0086]Equilibrium dissociation constants (KD values) for antigen binding to the selected antibodies described above were determined by surface kinetics on a real-time biosensor surface plasmon resonance assay (BIACORE® 2000). The antibody was captured on a goat anti-mouse IgG polyclonal antibody surface created through direct chemical coupling to a BIACORE® chip to form a captured antibody surface. Varying concentrations of monomeric hDll4 or dimeric hDll4-hFc were injected over the captured antibody surfaces, and antigen-antibody binding and dissociation monitored in real time. Kinetic analysis was performed to calculate KD, dissociation rate constants, and half-life of antigen/antibody complex dissociation (Table 1). A similar method was applied to measure single B cell-derived monoclonal antibodies modified to contain a human IgG constant domain. Antibodies were presented by goat anti-hFc polyclonal antibody reagent (Jackson Immuno Research Lab) immobilized on BIACORE® chip, and exposed to either dimeric Dll4-mFc or monomeric Dll4 protein (Table 2).
[0087]Antibody-antigen binding affinity may also be assessed using an ELISA based solution competition assay. Briefly, on a 96-well microtiter plate, antibodies (purified proteins or in conditioned medium) were premixed with serial dilutions of antigen protein (monomeric or dimeric) ranging from 0 to 10 μg/ml with a constant concentration of antibody. After a 2 hr incubation of antigen with antibody, the solutions were transferred to a microtiter plate precoated with antigen for measurement of free antibody (MAXISORB®, VWR, West Chester, Pa.). The plate was coated with 1 μg/ml hDll4-hFc protein in PBS solution overnight at 4° C. and nonspecific binding sites blocked with BSA for 2 hrs. After a 1 hr incubation following transfer, the plate was washed and the plate-bound antibodies were detected with an HRP-conjugated goat anti-mouse IgG polyclonal antibody reagent (Jackson Immuno Laboratory) and developed using colorimetric substrates (OPTEIA®; BD Biosciences Pharmingen, San Diego, Calif.). The enzymatic reaction was stopped with 1 M phosphoric acid, optical absorptions at 450 nm were recorded and the data were analyzed using a sigmoidal dose-response model and an IC50 values were reported (Table 1).
TABLE-US-00001 TABLE 1 Antibody KD DII4 (nM) KD DII4-Fc (nM) IC50 DII4-Fc (nM) 13B6 2.79 0.188 0.06 15E10 0.55 0.023 0.58 22G12 1.29 0.076 0.03 24C8 0.52 0.047 0.01 VAV 2H4-19 1.51 0.611 0.10 VAV 4H10-9 13.70 0.662 0.30 VAV 7B9-9 0.88 0.021 0.27 VAW 10E4-9 89.00 0.468 0.06 VAW 10G11-2 31.30 1.430 1.66 VAW 1C6-1 45.80 0.092 0.25 VAW 1G2-4 83.80 0.035 0.40 VAW 1H2-2 67.00 0.148 0.30 VAW 2H3-2 0.30 0.150 0.26 VAW 3A7-2 1.64 0.162 0.02 VAW 3A9-5 NA 2.510 16.00 VAW 3F12-8 8.12 0.648 0.07 VAW 6B8-12 0.89 0.060 0.43 VAW 6C6-2 91.70 0.092 0.50 VAW 6G12-10 3.74 0.527 0.19 VAW 7C10-11 17.10 0.853 0.28 VAW 8A10-14 1.41 0.648 0.08 VAW 8G1-12 6.09 8.300 8.60 VAW 9B11-2 62.20 0.048 0.00 VAW 9F12-6 16.00 1.350 0.02 VAW 9G10-1 56.10 0.555 0.10
TABLE-US-00002 TABLE 2 Antibody KD DII4 (nM) KD DII4-Fc (nM) 314266-06F12-B7 2.17 0.075 318518-01A04-D5 0.237 0.244 318518-01A10-D8 0.399 0.018 318518-01B09-C3 0.833 0.180 318518-01B11-D4 0.382 0.088 318518-01E07-H2 0.165 0.238 318518-01G04-F3 0.501 0.107 318518-01G05-B5 1.06 0.196 318518-02A07-B3 0.208 0.148 318518-02B06-E2 2.15 0.193 318518-02B08-F7 N/A N/A 318518-02C04-D1 0.478 0.331 318518-02F05-D10 1.28 0.035 318518-02G03-F2 1.31 0.042 318518-02G04-B11 0.813 0.048 318518-02G08-F11 N/A N/A 318518-03A03-B2 0.136 0.124 318518-03C10-F2 1.18 0.131 318518-03D04-B5 0.904 0.136 318518-03D07-G11 3.74 0.163 318518-03F04-A6 0.501 0.088 318518-03F06-A3 0.556 0.037 318518-03H03-F3 8.89 0.084 318518-14A06-E7 4.54 0.282 318518-14A07-C4 0.235 0.035 318518-14D08-G1 0.541 0.046 318518-14H08-A2 6.67 0.128 318518-1H08-E9 0.225 0.050
Example 3
Inhibition of Dll4 and Notch Interaction
[0088]The ability of the antibodies to block Dll4 binding to Notch was evaluated with an ELISA-based immunoassay. Briefly, Notch-hFc recombinant protein was coated on a 96-well plate in PBS buffer overnight at 4° C. at 1 mg/ml, and the nonspecific binding sites were blocked with BSA. This plate was used to measure free biotin-Dll4-hFc from antibody titration sample solutions. To make the antibody titration samples, a constant amount of biotin-Dll4-hFc at 25 pM was pre-mixed with varied amounts of antibody, either in crude hybridoma condition medium or as purified antibody protein, ranging from 0 to ˜50 nM in serial dilutions, followed by 2 hr incubation at room temperature to allow antibody-antigen binding to reach equilibrium. The equilibrated sample solutions were then transferred to the Notch-hFc coated plates for the measurement of free biotin-Dll4-hFc. After 1 hour binding, the plate was washed and bound biotin-Dll4-hFc was detected using HRP conjugated streptavidin (Poly HRP streptavidin, Pierce Endogen), and developed using TMB substrate (BD Pharmigen). Data was analyzed using GraphPad Prism software and IC50 values were determined as the amount of antibody required to achieve 50% reduction of biotin-Dll4-hFc bound to the plate-coated Notch-Fc (Table 3) (*conditioned media).
TABLE-US-00003 TABLE 3 Antibody IC50 (nM) VAV 2H4-19 0.01 VAW 3A7-2 0.017 VAW 9G10-1 0.019 VAW 10E4-9 0.032 VAW 8A10-11 0.04 VAW 9F12-6 0.059 VAW 3F12-8 0.066 VAW 1C6-1 0.086 VAW 1G2-4 0.11 VAW 6C6-2 0.119 VAV 7B9-4 0.123 VAW 1H2-2 0.154 VAW 2H3-2 0.168 VAW 6B8-12 0.255 VAW 6G12-10 0.257 VAW 7C10-11 0.273 VAV 4H10-9 0.599 VAW 10G11-2 0.931 VAW 3A9-5 3.8 VAW 8G1-12 10.7 VAW 9B11-2 0.069 15E10* 0.04 22G12 0.10 13B6 0.11 24C8 0.031 314266-06F12-B7 0.07 318518-01A04-D5 0.11 318518-01A10-D8 0.05 318518-01B09-C3 0.03 318518-01B11-D4 0.03 318518-01E07-H2 1.17 318518-01G04-F3 0.02 318518-01G05-B5 1.08 318518-02A07-B3 0.03 318518-02B06-E2 0.09 318518-02B08-F7 N/A 318518-02C04-D1 0.60 318518-02F05-D10 0.16 318518-02G03-F2 0.07 318518-02G04-B11 1.09 318518-02G08-F11 N/A 318518-03A03-B2 0.57 318518-03C10-F2 0.12 318518-03D04-B5 0.04 318518-03D07-G11 0.45 318518-03F04-A6 0.01 318518-03F06-A3 0.02 318518-03H03-F3 0.17 318518-14A06-E7 0.04 318518-14A07-C4 0.02 318518-14D08-G1 0.14 318518-14H08-A2 0.25 318518-1H08-E9 0.03
[0089]The ability of selected purified anti-hDll4 antibodies to block Dll4 binding to Notch was also evaluated with the ELISA-based immunoassay described above, modified by replacing 25 pM of biotin-Dll4-hFc with 30 pM of biotin-Dll4-hFc, and reducing antibody-antigen incubation duration from 2 hrs to 1 hr. For convenience, antibody 318518-01A10-D8 was renamed "REGN281" (HCVR/LCVR SEQ ID NOs:429/437 and hIgG1 SEQ ID NO:950). Derived antibodies tested included REGN421 (HCVR/LCVR SEQ ID NO:901/903, hIgG1 SEQ ID NO:950); and REGN422 (HCVR/LCVR SEQ ID NO:901/903, with modified hIgG4 SEQ ID NO:952). Results are shown in Table 4.
TABLE-US-00004 TABLE 4 Antibody IC50 (nM) REGN281 0.042 REGN421 0.045 REGN422 0.039
[0090]Ability of antibody to neutralize Dll4 mediated cellular function was also tested in vitro using Dll4 expressing human umbilical vein endothelial cells (HUVEC). Inhibition of Notch mediated hHes1 and EphB2 gene expression in HUVEC with the derived antibodies was monitored as follows: low passage HUVEC were cultured in MCDB-131 media (Vec Technologies). One day prior to analysis, HUVEC cells were seeded at a density of 2×105 cells/well in 24-well plates in 1 ml total media volume. The test antibody or other inhibitor was added directly to the individual sample wells in triplicate followed by 5-hour culture at 37° C. At the end of the culture period, media was removed and total RNA was isolated using QIAZOL® and the RNEASY® lipid tissue kit (Qiagen). mRNA level quantification was performed by the use of PCR and the fluorogenic 5' nuclease assay (TAQMAN® assay, Applied Biosystems). For each sample, cDNA was synthesized from 1-2 mg of total RNA. cDNA generated from an equivalent amount of starting RNA (typically 25 ng) was loaded in triplicate on ABI PRISM® optical reaction plates. For each RNA sample a "no RT" control was also run in which no reverse transcriptase was added to allow for subtraction of any potential genomic DNA contributions to the signal. 2× Mastermix (TAQMAN® 2×PCR Mastermix; ABI) was added to each reaction to a final concentration of 1×. Additionally, TAQMAN® probe and primers for the gene of interest were added to each reaction. Each primer was used at a final concentration of 900 nM and the probe was added at a final concentration of 200 nM. Human genomic DNA was used as a standard. The assays were performed under standard TAQMAN® conditions on a ABI 7900HT instrument. Levels of Hes1 and EphrinB2 were measured and normalized to an endogenous control gene (cyclophilin) (Table 5). Probes and primers: human Hes1 probe (SEQ ID NO:387); Oligos: hHes1-869F (SEQ ID NO:388); hHes1-940R (SEQ ID NO:389), human ephrinB2 probe: hEphB2-773T (SEQ ID NO:390); Oligos: hEphB2-752F (SEQ ID NO:391) hEphB2-812R (SEQ ID NO:392); human cyclophilin: probe: hCyclophilin-343T (SEQ ID NO:393); Oligos: hCyclophilin-323F (SEQ ID NO:394); hCyclophilin-389R (SEQ ID NO:395).
TABLE-US-00005 TABLE 5 EphrinB2 Expression Hes1 Expression Antibody IC50 (nM) IC50 (nM) 22G12 0.379 0.381 15E10 2.56 4.49 VAW 3A7-2 0.409 0.533 314266-06F12-B7 0.239 0.405 318518-01A10-D8 0.305 0.329 318518-01G04-F3 0.088 0.172 318518-01H08-E9 0.413 0.548 318518-02A07-B3 0.398 0.128 318518-03F04-A6 0.158 0.115 318518-03F06-A3 0.304 0.692 318518-014A07-C4 0.175 0.312 318518-014D08-G1 0.510 0.568 hDII4-hFc 0.843 0.974
[0091]HUVEC Proliferation Assay. The ability of antibody to block Dll4 mediated growth inhibition of Human umbilical vein endothelial cells (HUVEC) cells was tested in an in vitro cell proliferation assay. Low passage HUVEC cells were obtained and cultured in MCDB-131 media (Vec Technologies). One day prior to analysis 12-well tissue culture plates were coated with hDll4-hFc in PBS at 4° C. overnight (0.2 μg/ml; 0.5 ml PBS/well). Plates were washed 1× with PBS and HUVEC cells were seeded at a density of 4×103 cells/well in 1.0 ml total media volume. Immediately following addition of cells anti-hDll4 antibodies were added in 0.5 ml total volume over a range of concentrations to generate an inhibition curve. Cells were grown for 96-hours at 37° C. Cell number was quantitated using the CCK-8 reagent (Dojindo). All assays were run in triplicate. (Table 6, NB, not blocking).
TABLE-US-00006 TABLE 6 Antibody IC50 (nM) 15E10 0.284 VAW9B11-2 1.868 VAW8D8-12 NB 13B6 5.01 VAW2H4-19 NB VAW3A7-2 0.198 VAW8A10-14 0.214 22G12 0.888 318518-06F12-B7 2.067 318518-01A10-D8 0.096 318518-01G04-F3 0.106 318518-01H08-E9 0.188 318518-02A07-B3 0.200 318518-03F04-A6 0.184 318518-03F06-A3 0.188 318518-014A07-C4 0.159 318518-014D08-G1 0.165
[0092]Notch-Inducible Luciferase Assay. A bioassay was developed to determine the ability of selected purified antibodies to neutralize Dll4-mediated cellular function in vitro using an engineered HEK293 cell line (ATCC) that constitutively expresses human Notch 1 and contains a Notch-responsive promoter driving luciferase. Inhibition of Notch-inducible luciferase activity was determined as follows: 1 day prior to assay, each well of an opaque 96 well tissue culture plate was coated with 100 μl of either 1 nM or 1.5 nM hDll4-hFc in PBS overnight at 4° C. Cells were seeded onto the coated plates at 2×104 cells/well in media. Purified antibody protein, in serial dilutions starting from 2 nM in cell media, was incubated with the cells at 37° C. for 24 hrs. Luciferase activity was determined by adding an equal well volume of STEADY-GLO® Substrate (Promega) (Table 7).
TABLE-US-00007 TABLE 7 IC50 (pM) Antibody 1 nM hDII4-hFc 1.5 nM hDII4-hFc REGN281 50.5 78.7 REGN421 54.4 87.3 REGN422 88.2 131.1
Example 4
Inhibition of Notch1 Cleavage
[0093]The ability of selected anti-hDll4 antibodies to inhibit Notch1 cleavage was tested by examination of total cleaved Notch1 protein by SDS-Page/Western blotting. Low passage HUVEC cells were cultured as described above. One day prior to analysis 6-well plates were coated with hDll4-hFc in PBS at 4° C. overnight (0.2 μg/ml; 1.0 ml PBS/well). Plates were washed 1× with PBS and HUVEC cells were seeded at 7.5×105 cells/well in 2.0 ml total media volume. Immediately following cell seeding, anti-hDll4 antibody was added to each well at 10 nM final concentration. Cells were grown for 24 hours at 37° C. following which whole cell extracts were prepared and analyzed by SDS-PAGE. Levels of cleaved Notch1 were determined using an anti-cleaved Notch1 (Val1744) antibody (Cell Signaling) and standard western blotting techniques. The anti-hDll4 antibodies were able to entirely block the Notch1 cleavage induced by plate coated hDll4-hFc (data not shown).
Example 5
ADCC and CDC Assays
[0094]Antibody-dependent cell-mediated cytotoxicity (ADCC) induced by two test antibodies (REGN421, REGN422) was assessed using a panel of eight target cell lines with varying hDll4 expression levels. The eight target cell lines were (1) HUVECs; (2) HUVECs stimulated with 10 nM VEGF for 24 hours; (3) Colo205; (4) engineered C6 rat glioma cells expressing eGFP; (5) engineered C6 rat glioma cells expressing hDll4; (6) engineered HT1080 cells expressing eGFP; (7) engineered HT1080 cells expressing hDll4; and (8) HT29. Human Dll4 or eGFP was integrated into the C6 cell or HT1080 genome through retroviral transfection. Briefly, cells from each target cell line (10,000 cells/well in 50 μl) were first mixed with an equal volume of serially diluted REGN421 or REGN422, resulting in a final antibody concentration ranging from 0.169 pM to 10 nM, and incubated for 10 min at room temperature in a 96-well plate format (control=wells without antibody). Separately, human peripheral blood mononuclear cells (PBMCs, effector cells) were prepared following a conventional Ficoll-Hypaque gradient centrifugation enrichment procedure. Approximately 300,000 PBMCs were added to each mixture of antibody and target cells to give a final ratio of effector to target cells of approximately 30:1. The 96-well plates were then incubated for 4 h at 37° C., 5% CO2 followed by centrifugation at 250×g. Supernatants were harvested and assayed for lactate dehydrogenase (LDH) activity using the CYTOTOX 96® Non-Radioactive Cytotoxicity Assay system (Promega). Results are shown in Table 8. REGN421-induced dose dependent cell lysis was only observed in C6 cells expressing hDll4 (col. 5), which exhibited the highest hDll4 expression among all cell lines (as determined by immunoprecipitation/Western blot and flow cytometry). The maximum cell cytotoxicity in the C6-hDll4 cell line ranged from 20% to 60%. No REGN421-induced cell lysis was observed in the remaining seven target cell lines. REGN422 did not induce cell lysis in any of the target cell lines.
TABLE-US-00008 TABLE 8 % Maximum Cytotoxicity Ab 1 2 3 4 5 6 7 8 REGN421 0 0 0 0 20-60 0 0 0 REGN422 0 0 0 0 0 0 0 0
[0095]Complement-dependent cytotoxicity (CDC) induced by REGN421 was assessed using the same panel of cells lines described above. Briefly, cells from each of the target cell lines (50,000 cells/well in 50 μl) were first mixed with an equal volume of serially diluted REGN421, resulting in a final antibody concentration ranging from 0.169 pM to 10 nM, and incubated for 10 min at room temperature in a 96-well plate format. Normal human serum, with complement components (Quidel Corp., San Diego, Calif.) was added to each well to give a final serum concentration of 5%. The plates were then incubated at 37° C., 5% CO2 for 2 hours followed by addition of CELLTITER-BLUE® reagent (Promega) (controls=wells without antibody and wells with antibody but no serum). The plates were incubated overnight and cell survival (CDC levels) assayed. As a positive control, Daudi cells were treated with rituximab. REGN421 exhibited no CDC toward any of the target cell lines tested (data not shown).
Example 6
Epitope Mapping and Specificity
[0096]In order to determine epitope binding specificity, a series of seven chimeric Dll4 proteins were generated in which specific human Dll4 domains were substituted into a mouse Dll4 protein as follows: #1 contained the human N-terminal and DSL domains (S27-Q218); #2 contained human N-terminal, DSL and EGF-1 domains (S27-N252); #3 contained human N-terminal, DSL, EGF-1 and EGF-2 domains (S27-Q283); #4 contained human N-terminal, DSL, EGF-1, EGF-2, EGF-3, EGF-4 and EGF-5; #5 contained human N-terminal domain (S27-R172); #6 contained human DSL domain (V173-Q218); and #7 contained human EGF-2 domain (E252-D282). The chimeric proteins were fused to a mouse IgG2a-Fc fragment and expressed in CHO-K1 cell. The conditioned media were harvested and protein expression confirmed by western blot.
[0097]Binding specificity of test antibodies to hDll4, mDll4, and chimeric proteins #1, #2, #3, and #4 were tested as follows: purified antibodies 22G12, VAW3A7-2, and 15E10 were amine coupled between 5000-6000 RU on CM5 chip. Conditioned media from CHO K1 cells containing the chimeric Dll4 proteins, hDll4-mFc, and mDll4-mFc were injected sequentially followed by surface regeneration over antibody-coupled surfaces. A blank amine coupled flowcell surface was used as a control for nonspecific binding of the conditioned media. Results are summarized in Table 9. 22G12 bound an epitope between S27-Q218 of hDll4; VAW3A7-2 bound an epitope between Q283-E400 hDll4; and 15E10 bound an epitope between E252-D282 of hDll4.
TABLE-US-00009 TABLE 9 Chimeric Proteins Antibody hDII4-mFc mDII4-mFc #1 #2 #3 #4 22G12 + - + + + + VAW3A7-2 + - - - - + 15E10 + - - - + +
[0098]Binding specificity of purified test mAb to hDll4, mDll4 and the chimeric proteins (described above) was determined (REGN279=314266-6F12-B7; REGN287=318518-1G04-F3; REGN289=318518-1H08-E9; REGN290=318518-2A07-B3; REGN306=318518-3F06-A3). Briefly, each D114 protein was captured (70-130 RU) on goat anti-mouse IgG antibody surfaces, followed by injection of test mAb at a concentration of 100 μg/ml. An antibody that bound mDll4-mFc was used as a positive control (positive control=6C10). The results (Table 10) show that REGN279 bound an epitope between S27-Q218 of hDll4; REGN287 bound between Q283-E400 of hDll4; REGN289, REGN290 and REGN306 bound between S27-E400 of hDll4.
TABLE-US-00010 TABLE 10 Chimeric human-mouse DII4 Fusion Proteins Antibody hDII4-mFc mDII4-mFc #1 #2 #3 #4 #5 #6 #7 REGN279 + - + + + + + - - REGN287 + - - - - + - - - REGN289 + - + + + + - + - REGN290 + - + + + + - + - REGN306 + - + + + + - + - Control + + + + + + + + +
[0099]Further epitope binding specificity determinations were conducted as described above with the following purified test antibodies: REGN281=318518-1A10-D8; REGN305=318518-3F04-A6; REGN309=318518-14A07-C4; REGN310=318518-14D08-G1; REGN421, and REGN422. Briefly, each of the Dll4 proteins was captured (240-470 RU) on goat anti-mouse IgG antibody surfaces, followed by injection of test antibody at a concentration of 100 μg/ml (Table 11).
TABLE-US-00011 TABLE 11 Chimeric human-mouse DII4 Fusion Proteins Antibody hDII4-mFc mDII4-mFc #1 #2 #3 #4 #5 #6 #7 REGN281 + - + + + + + + - REGN305 + - - - - + - - - REGN309 + - + + + - + + - REGN310 + - - - + + - + + REGN421 + - + + + + + + - REGN422 + - + + + + + + -
[0100]Western blot analysis. Binding specificity of selected antibodies to chimeric, mouse and human Dll4 was determined by Western blot. Briefly, hDll4-mFc (200 ng per lane), mDll4-mFc (200 ng per lane), and chimeric proteins #1-#7 (approximate 150 ng per lane) were subjected to electrophoresis on duplicate SDS-PAGE gels using non-reducing sample buffer. Each gel was then transferred to a PVDF membrane. Blots were first exposed to REGN421 at 0.2 μg/ml and then to HRP-conjugated anti-hIgG antibody (Pierce). Control blots were exposed to HRP-conjugated anti-mFc antibody (Pierce). Results: REGN421 recognized hDll4-mFc and chimeric proteins containing the human N-terminal domain (#5), a human DSL domain (#6), or both (#1, #2, #3, and #4). REGN421 did not recognize a chimeric protein containing a human EGF-2 domain (#7).
[0101]Protease digestion analysis. Binding between REGN281 and hDll4 was further assessed by protective protease digestion and liquid chromatography/mass spectrometry (LC/MS) using an HPLC1100 (Agilent) and LCQ Classical Ion Trap Mass Spectrometer (Thermo). Briefly, a mixture of hDll4 and REGN281, in a molar ratio of 1:5, or hDll4 alone, was incubated with protease overnight at either 25° C. (for GluC protease) or 37° C. (for trypsin). Each of the resulting proteolytic digest mixtures was then subjected to LC/MS. Unique peptide peaks present in proteolytic digests performed in the absence of REGN281, which either diminished or disappeared in proteolytic digests performed in the presence of REGN281, indicate potential REGN281 binding sites on hDll4 that were protected from protease digestion by the binding of REGN281 to hDll4. These unique peptide peaks were analyzed by mass spectrometry. The observed mass, predicted mass, and the N-terminal sequences of the peptides are shown in Table 12.
TABLE-US-00012 TABLE 12 Observed Predicted hDII4 Peptide Peak Mass Mass (SEQ ID NO: 2) Protease Domain G1 521 521.5 Phe37-Glu40 GluC N-terminal G2 1362.8 1363.4 Ala121-Glu132 GluC N-terminal T1 758 760.8 Pro49-Arg55 Trypsin N-terminal T2 587.1 587.2 Tyr169-Arg172 Trypsin N-terminal T3 1607.4 1607.6 Val173-Arg186 Trypsin DSL T4 1399 1400.7 Gly42-Arg55 Trypsin N-terminal T5 569.2 569.3 Thr56-Arg59 Trypsin N-terminal T7 2615 2613.4 Ile143-Arg166 Trypsin N-terminal T8 1807.2 1806.9 Ser27-Arg41 Trypsin N-terminal
Example 7
Binding Affinity of Purified Antibodies to Human and Monkey Dll4
[0102]The binding affinities of selected purified antibodies to hDll4, M. facscicularis Dll4 (mfDll4, SEQ ID NO:956), and M. mulatta Dll4 (mmDll4, SEQ ID NO:957) monomers were determined using a BIACORE® 2000 & 3000. Goat anti-hFc polyclonal antibody reagent immobilized on a BIACORE® chip was used to present REGN281, REGN421, and REGN422. Varying concentrations of each proteins, hDll4 (from 12.5 nM to 100 nM), mfDll4 (from 3.13. nM to 100 nM), or mmDll4 (from 12.5 nM to 100 nM) were used as analyte, and injected over the antibody surfaces. Antigen-antibody binding and dissociation of bound complex were monitored in real time (Table 13).
TABLE-US-00013 TABLE 13 ka (M-1s-1) kd (s-1) KD (nM) hDII4 mfDII4 mmDII4 hDII4 mfDII4 mmDII4 hDII4 mfDII4 mmDII4 REGN281 1.56 × 105 6.64 × 104 9.27 × 104 2.30 × 10-5 2.04 × 10-5 3.05 × 10-5 0.148 0.307 0.329 REGN421 1.63 × 105 7.28 × 104 9.70 × 104 2.17 × 10-5 2.02 × 10-5 3.23 × 10-5 0.133 0.278 0.333 REGN422 1.64 × 105 8.01 × 104 9.27 × 104 2.36 × 10-5 2.88 × 10-5 3.41 × 10-5 0.144 0.360 0.375
[0103]The binding affinities of anti-hDll4 antibodies toward hDll4 and mmDll4 dimers were also determined using a BIACORE® 2000 and the method describe above, except that hDll4 was replaced with hDll4-mFc (from 3.13 nM to 100 nM), or mmDll4 with mmDll4-mFc (from 0.78 nM to 25 nM) as analyte (Table 14).
TABLE-US-00014 TABLE 14 ka (M-1s-1) kd (s-1) KD (nM) hDII4-mFc mmDII4-mFc hDII4-mFc mmDII4-mFc hDII4-mFc mmDII4-mFc REGN281 3.02 × 105 3.16 × 105 4.96 × 10-6 4.64 × 10-6 0.0163 0.0147 REGN421 3.43 × 105 3.35 × 105 4.70 × 10-6 3.80 × 10-6 0.0137 0.013 REGN422 3.46 × 105 4.23 × 105 4.60 × 10-6 4.15 × 10-6 0.0133 0.0098
Example 8
Cross-Reactivity of Antibodies With hDll1, hDll3, mDll4, or mfDll4
[0104]Cross-reactivity of the antibodies to human delta-like ligand1 (SEQ ID NO:953) and human delta-like ligand 3 (SEQ ID NO:954) proteins was determined. REGN281, REGN421 and REGN422 were presented by a goat anti-human kappa (hK) polyclonal antibody reagent (Southern Biotech) immobilized on a BIACORE® chip, and either hDll4-hFc or hDll1-hFc protein at 100 μg/ml were used as analyte injected over the antibody surfaces. All three anti-hDll4 antibodies only bound to hDll4-hFc, and did not bind hDll1-hFc.
[0105]An alternative BIACORE® format was used to assess cross-reactivity between anti-hDll4 antibody and either hDll1-hFc or hDll3-hFc. Briefly, ligands hDll4-hFc, hDll1-hFc, and hDll3-hFc were each covalently linked to a CM-5 chip, through amine coupling, to an RU range of about 8,000 to 10,000. REGN421, at 300 μg/ml, was injected over the surface of each chip. REGN421 bound only to hDll4-hFc; no binding was observed to either hDll1-hFc or hDll3-hFc. The same result was observed for REGN422 instead of REGN421.
[0106]OCTET®-based binding assays were employed to determine the binding between selected purified anti-hDll4 antibodies and hDll4-hFc, hDll3-hFc, hDll1-hFc, mfDll4-mmh, or mDll4-mFc. Briefly, strepavidin high binding FA biosensors (ForteBio, Inc., Menlo Park, Calif.) were first incubated with biotin-anti-hK at 5 μg/ml for 10 min at 30° C., to achieve saturation. Biotin-anti-hK-bound biosensors were then incubated with antibodies REGN281, REGN421 or REGN422, at 20 pg/ml for 10 min at 30° C., to achieve saturation. The antibody-bound biosensors were then incubated with either hDll4-hFc or hDll3-hFc, hDll1-hFc, or mDll4-mFc, at 200 nM, or mfDll4-mmh at 100 nM, for 10 min at 30° C. Changes in the thickness of the biological layer after each incubation were measured. Human Dll4-hFc and mfDll4-mmh bound to anti-hDll4 antibody-bound biosensors, whereas hDll3-hFc, hDll1-hFc, and mDll4-mFc did not bind to anti-hDll4 antibody-bound biosensors.
Example 9
Effect of Anti-hDll4 Antibody on Tumor Growth
[0107]The effect of REGN421 on tumor growth was evaluated on tumors implanted in Severe Combined Immunodeficiency (SCID) mice expressing a humanized Dll4 protein (SCID×hDll4). Briefly, the humanized Dll4 mouse was made by replacing the entire extracellular domain of the mouse Dll4 gene with the corresponding extracellular region of the human Dll4 gene (7 kb) in embryonic stem (ES) cells. Homozygous hDll4 mice were generated and bred into SCID background. Each mouse was then implanted subcutaneously (SC) with 2.5×106 human HT1080 tumor cells. After the tumors were established in the mice (˜100-150 mm3 18 days after implantation), mice were measured and treated with hFc, hDll4-Fc or REGN421. A total of 7 mice were divided into three groups. The first group (n=3) was treated subcutaneously with hFc at 25 mg/kg; the second group (n=1) was treated with hDll4-Fc at 25 mg/kg; and the third group (n=3) was treated with REGN421 at 10 mg/kg. The treatments were repeated every 48 hours starting at day 18. In vivo tumor measurements were obtained three days before the initial treatment (day 15), on the same day of each treatment (days 18, 20, and 22), and on day 25. Tumor size was calculated using the formula I×w2/2. Results are shown in Table 15. On day 25, mice were euthanized and each tumor was removed and measured ex vivo and calculated (length×width×depth) (Table 16).
[0108]In addition, a group of SCID mice expressing endogenous mDll4 (n=2) was implanted with tumor cells and treated with hDll4-Fc (25 mg/kg) following the same dosing schedule.
TABLE-US-00015 TABLE 15 Tumor Size (mm3) Mouse Treatment Day 15 Day 18 Day 20 Day 22 Day 25 SCID hDII4-hFc 162.0 232.8 320.0 336.0 253.1 SCID hDII4-hFc 22.5 117.0 117.0 108.0 68.8 SCIDxhDII4 hDII4-hFc 288.0 320.0 352.0 446.0 320.0 SCIDxhDII4 hFc 162.0 288.0 320.0 500.0 550.0 SCIDxhDII4 hFc 162.0 220.5 352.0 662.0 661.5 SCIDxhDII4 hFc 93.8 135.0 179.6 352.0 726.0 SCIDxhDII4 REGN421 144.0 245.0 320.0 162.0 144.0 SCIDxhDII4 REGN421 87.5 162.0 153.0 225.0 135.0 SCIDxhDII4 REGN421 144.0 196.0 272.0 162.0 152.5
TABLE-US-00016 TABLE 16 Mouse Treatment Tumor Size (mm3) SCID hDII4-hFc 308.0 SCID hDII4-hFc 105.0 SCIDxhDII4 hDII4-hFc 480.0 SCIDxhDII4 hFc 924.0 SCIDxhDII4 hFc 1020.0 SCIDxhDII4 hFc 792.0 SCIDxhDII4 REGN421 168.0 SCIDxhDII4 REGN421 84.0 SCIDxhDII4 REGN421 189.0
Sequence CWU
1
95712058DNAHomo sapiens 1atggcggcag cgtcccggag cgcctctggc tgggcgctac
tgctgctggt ggcactttgg 60cagcagcgcg cggccggctc cggcgtcttc cagctgcagc
tgcaggagtt catcaacgag 120cgcggcgtac tggccagtgg gcggccttgc gagcccggct
gccggacttt cttccgcgtc 180tgccttaagc acttccaggc ggtcgtctcg cccggaccct
gcaccttcgg gaccgtctcc 240acgccggtat tgggcaccaa ctccttcgct gtccgggacg
acagtagcgg cggggggcgc 300aaccctctcc aactgccctt caatttcacc tggccgggta
ccttctcgct catcatcgaa 360gcttggcacg cgccaggaga cgacctgcgg ccagaggcct
tgccaccaga tgcactcatc 420agcaagatcg ccatccaggg ctccctagct gtgggtcaga
actggttatt ggatgagcaa 480accagcaccc tcacaaggct gcgctactct taccgggtca
tctgcagtga caactactat 540ggagacaact gctcccgcct gtgcaagaag cgcaatgacc
acttcggcca ctatgtgtgc 600cagccagatg gcaacttgtc ctgcctgccc ggttggactg
gggaatattg ccaacagcct 660atctgtcttt cgggctgtca tgaacagaat ggctactgca
gcaagccagc agagtgcctc 720tgccgcccag gctggcaggg ccggctgtgt aacgaatgca
tcccccacaa tggctgtcgc 780cacggcacct gcagcactcc ctggcaatgt acttgtgatg
agggctgggg aggcctgttt 840tgtgaccaag atctcaacta ctgcacccac cactccccat
gcaagaatgg ggcaacgtgc 900tccaacagtg ggcagcgaag ctacacctgc acctgtcgcc
caggctacac tggtgtggac 960tgtgagctgg agctcagcga gtgtgacagc aacccctgtc
gcaatggagg cagctgtaag 1020gaccaggagg atggctacca ctgcctgtgt cctccgggct
actatggcct gcattgtgaa 1080cacagcacct tgagctgcgc cgactccccc tgcttcaatg
ggggctcctg ccgggagcgc 1140aaccaggggg ccaactatgc ttgtgaatgt ccccccaact
tcaccggctc caactgcgag 1200aagaaagtgg acaggtgcac cagcaacccc tgtgccaacg
ggggacagtg cctgaaccga 1260ggtccaagcc gcatgtgccg ctgccgtcct ggattcacgg
gcacctactg tgaactccac 1320gtcagcgact gtgcccgtaa cccttgcgcc cacggtggca
cttgccatga cctggagaat 1380gggctcatgt gcacctgccc tgccggcttc tctggccgac
gctgtgaggt gcggacatcc 1440atcgatgcct gtgcctcgag tccctgcttc aacagggcca
cctgctacac cgacctctcc 1500acagacacct ttgtgtgcaa ctgcccttat ggctttgtgg
gcagccgctg cgagttcccc 1560gtgggcttgc cgcccagctt cccctgggtg gccgtctcgc
tgggtgtggg gctggcagtg 1620ctgctggtac tgctgggcat ggtggcagtg gctgtgcggc
agctgcggct tcgacggccg 1680gacgacggca gcagggaagc catgaacaac ttgtcggact
tccagaagga caacctgatt 1740cctgccgccc agcttaaaaa cacaaaccag aagaaggagc
tggaagtgga ctgtggcctg 1800gacaagtcca actgtggcaa acagcaaaac cacacattgg
actataatct ggccccaggg 1860cccctggggc gggggaccat gccaggaaag tttccccaca
gtgacaagag cttaggagag 1920aaggcgccac tgcggttaca cagtgaaaag ccagagtgtc
ggatatcagc gatatgctcc 1980cccagggact ccatgtacca gtctgtgtgt ttgatatcag
aggagaggaa tgaatgtgtc 2040attgccacgg aggtataa
20582685PRTHomo sapiens 2Met Ala Ala Ala Ser Arg
Ser Ala Ser Gly Trp Ala Leu Leu Leu Leu1 5
10 15Val Ala Leu Trp Gln Gln Arg Ala Ala Gly Ser Gly Val
Phe Gln Leu20 25 30Gln Leu Gln Glu Phe
Ile Asn Glu Arg Gly Val Leu Ala Ser Gly Arg35 40
45Pro Cys Glu Pro Gly Cys Arg Thr Phe Phe Arg Val Cys Leu Lys
His50 55 60Phe Gln Ala Val Val Ser Pro
Gly Pro Cys Thr Phe Gly Thr Val Ser65 70
75 80Thr Pro Val Leu Gly Thr Asn Ser Phe Ala Val Arg
Asp Asp Ser Ser85 90 95Gly Gly Gly Arg
Asn Pro Leu Gln Leu Pro Phe Asn Phe Thr Trp Pro100 105
110Gly Thr Phe Ser Leu Ile Ile Glu Ala Trp His Ala Pro Gly
Asp Asp115 120 125Leu Arg Pro Glu Ala Leu
Pro Pro Asp Ala Leu Ile Ser Lys Ile Ala130 135
140Ile Gln Gly Ser Leu Ala Val Gly Gln Asn Trp Leu Leu Asp Glu
Gln145 150 155 160Thr Ser
Thr Leu Thr Arg Leu Arg Tyr Ser Tyr Arg Val Ile Cys Ser165
170 175Asp Asn Tyr Tyr Gly Asp Asn Cys Ser Arg Leu Cys
Lys Lys Arg Asn180 185 190Asp His Phe Gly
His Tyr Val Cys Gln Pro Asp Gly Asn Leu Ser Cys195 200
205Leu Pro Gly Trp Thr Gly Glu Tyr Cys Gln Gln Pro Ile Cys
Leu Ser210 215 220Gly Cys His Glu Gln Asn
Gly Tyr Cys Ser Lys Pro Ala Glu Cys Leu225 230
235 240Cys Arg Pro Gly Trp Gln Gly Arg Leu Cys Asn
Glu Cys Ile Pro His245 250 255Asn Gly Cys
Arg His Gly Thr Cys Ser Thr Pro Trp Gln Cys Thr Cys260
265 270Asp Glu Gly Trp Gly Gly Leu Phe Cys Asp Gln Asp
Leu Asn Tyr Cys275 280 285Thr His His Ser
Pro Cys Lys Asn Gly Ala Thr Cys Ser Asn Ser Gly290 295
300Gln Arg Ser Tyr Thr Cys Thr Cys Arg Pro Gly Tyr Thr Gly
Val Asp305 310 315 320Cys
Glu Leu Glu Leu Ser Glu Cys Asp Ser Asn Pro Cys Arg Asn Gly325
330 335Gly Ser Cys Lys Asp Gln Glu Asp Gly Tyr His
Cys Leu Cys Pro Pro340 345 350Gly Tyr Tyr
Gly Leu His Cys Glu His Ser Thr Leu Ser Cys Ala Asp355
360 365Ser Pro Cys Phe Asn Gly Gly Ser Cys Arg Glu Arg
Asn Gln Gly Ala370 375 380Asn Tyr Ala Cys
Glu Cys Pro Pro Asn Phe Thr Gly Ser Asn Cys Glu385 390
395 400Lys Lys Val Asp Arg Cys Thr Ser Asn
Pro Cys Ala Asn Gly Gly Gln405 410 415Cys
Leu Asn Arg Gly Pro Ser Arg Met Cys Arg Cys Arg Pro Gly Phe420
425 430Thr Gly Thr Tyr Cys Glu Leu His Val Ser Asp
Cys Ala Arg Asn Pro435 440 445Cys Ala His
Gly Gly Thr Cys His Asp Leu Glu Asn Gly Leu Met Cys450
455 460Thr Cys Pro Ala Gly Phe Ser Gly Arg Arg Cys Glu
Val Arg Thr Ser465 470 475
480Ile Asp Ala Cys Ala Ser Ser Pro Cys Phe Asn Arg Ala Thr Cys Tyr485
490 495Thr Asp Leu Ser Thr Asp Thr Phe Val
Cys Asn Cys Pro Tyr Gly Phe500 505 510Val
Gly Ser Arg Cys Glu Phe Pro Val Gly Leu Pro Pro Ser Phe Pro515
520 525Trp Val Ala Val Ser Leu Gly Val Gly Leu Ala
Val Leu Leu Val Leu530 535 540Leu Gly Met
Val Ala Val Ala Val Arg Gln Leu Arg Leu Arg Arg Pro545
550 555 560Asp Asp Gly Ser Arg Glu Ala
Met Asn Asn Leu Ser Asp Phe Gln Lys565 570
575Asp Asn Leu Ile Pro Ala Ala Gln Leu Lys Asn Thr Asn Gln Lys Lys580
585 590Glu Leu Glu Val Asp Cys Gly Leu Asp
Lys Ser Asn Cys Gly Lys Gln595 600 605Gln
Asn His Thr Leu Asp Tyr Asn Leu Ala Pro Gly Pro Leu Gly Arg610
615 620Gly Thr Met Pro Gly Lys Phe Pro His Ser Asp
Lys Ser Leu Gly Glu625 630 635
640Lys Ala Pro Leu Arg Leu His Ser Glu Lys Pro Glu Cys Arg Ile
Ser645 650 655Ala Ile Cys Ser Pro Arg Asp
Ser Met Tyr Gln Ser Val Cys Leu Ile660 665
670Ser Glu Glu Arg Asn Glu Cys Val Ile Ala Thr Glu Val675
680 6853358DNAArtificial SequenceSynthetic 3gaggtgcaac
tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag
cctctggatt cacctttagt acctattgga tgaactgggt ccgccaggct 120ccagggaagg
ggctggagtg ggtggccaac ataaaccaag atggaagtga gaaatactat 180gtggactctg
tgaagggccg aatcaccatc tccagagaca acgccaagaa ctcactgtat 240ctgcaaatga
acagcctgag agtcgaggac acggctgtat attactgtgc gagaaaatgg 300aacaactgga
acccggagga gaactggggc cagggaaccc tggtcaccgt ctcctcag
3584119PRTArtificial SequenceSynthetic 4Glu Val Gln Leu Val Glu Ser Gly
Gly Gly Leu Val Gln Pro Gly Gly1 5 10
15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr
Tyr20 25 30Trp Met Asn Trp Val Arg Gln
Ala Pro Gly Lys Gly Leu Glu Trp Val35 40
45Ala Asn Ile Asn Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val50
55 60Lys Gly Arg Ile Thr Ile Ser Arg Asp Asn
Ala Lys Asn Ser Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr
Cys85 90 95Ala Arg Lys Trp Asn Asn Trp
Asn Pro Glu Glu Asn Trp Gly Gln Gly100 105
110Thr Leu Val Thr Val Ser Ser115524DNAArtificial SequenceSynthetic
5ggattcacct ttagtaccta ttgg
2468PRTArtificial SequenceSynthetic 6Gly Phe Thr Phe Ser Thr Tyr Trp1
5724DNAArtificial SequenceSynthetic 7ataaaccaag atggaagtga gaaa
2488PRTArtificial
SequenceSynthetic 8Ile Asn Gln Asp Gly Ser Glu Lys1
5936DNAArtificial SequenceSynthetic 9gcgagaaaat ggaacaactg gaacccggag
gagaac 361012PRTArtificial
SequenceSynthetic 10Ala Arg Lys Trp Asn Asn Trp Asn Pro Glu Glu Asn1
5 1011337DNAArtificial SequenceSynthetic
11gatattgtga tgactcagtc tccactctcc ctgcccgtca cccctggaga gccggcctcc
60atctcctgca ggtctagtca gagcctcctg cataatagtg gatacaactt tttggattgg
120tacctgcaga agccagggca gtctccacaa ctcctgatct atttgcgttc taatcgggcc
180tccggggtcc ctgacaggtt cagtggcagt ggatcaggca cagattttac actgaagatc
240agaagagtgg aggctgagga tgttgggatt tattactgca tgcaagctct acacactcct
300tacacttttg gccaggggac caaggtggag atcaaac
33712112PRTArtificial SequenceSynthetic 12Asp Ile Val Met Thr Gln Ser Pro
Leu Ser Leu Pro Val Thr Pro Gly1 5 10
15Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His
Asn20 25 30Ser Gly Tyr Asn Phe Leu Asp
Trp Tyr Leu Gln Lys Pro Gly Gln Ser35 40
45Pro Gln Leu Leu Ile Tyr Leu Arg Ser Asn Arg Ala Ser Gly Val Pro50
55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr
Asp Phe Thr Leu Lys Ile65 70 75
80Arg Arg Val Glu Ala Glu Asp Val Gly Ile Tyr Tyr Cys Met Gln
Ala85 90 95Leu His Thr Pro Tyr Thr Phe
Gly Gln Gly Thr Lys Val Glu Ile Lys100 105
1101333DNAArtificial SequenceSynthetic 13cagagcctcc tgcataatag
tggatacaac ttt 331411PRTArtificial
SequenceSynthetic 14Gln Ser Leu Leu His Asn Ser Gly Tyr Asn Phe1
5 10159DNAArtificial SequenceSynthetic 15ttgcgttct
9163PRTArtificial SequenceSynthetic 16Leu Arg Ser11727DNAArtificial
SequenceSynthetic 17atgcaagctc tacacactcc ttacact
27189PRTArtificial SequenceSynthetic 18Met Gln Ala Leu
His Thr Pro Tyr Thr1 519376DNAArtificial SequenceSynthetic
19gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc
60tcctgtgtag cctctggatt cacctttagt agctattgga tgacctgggt ccgccaggct
120ccagggaagg ggctggagtg ggtggccaac ataaaacaag atggaagtga gaaatactat
180gtggactctg tgaagggccg attcaccgtc tccagagaca acgccaagaa ctcagtgtat
240ctgcaaatga gcagcctgag agccgaggac acggctgtgt attactgtgc gagagattgg
300aactatggcc ccgattacta ctactaccac ggtttggacg tctggggcca agggaccacg
360gtcaccgtct cctcag
37620125PRTArtificial SequenceSynthetic 20Glu Val Gln Leu Val Glu Ser Gly
Gly Gly Leu Val Gln Pro Gly Gly1 5 10
15Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Ser
Tyr20 25 30Trp Met Thr Trp Val Arg Gln
Ala Pro Gly Lys Gly Leu Glu Trp Val35 40
45Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val50
55 60Lys Gly Arg Phe Thr Val Ser Arg Asp Asn
Ala Lys Asn Ser Val Tyr65 70 75
80Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys85 90 95Ala Arg Asp Trp Asn Tyr Gly
Pro Asp Tyr Tyr Tyr Tyr His Gly Leu100 105
110Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser115
120 1252124DNAArtificial SequenceSynthetic 21ggattcacct
ttagtagcta ttgg
24228PRTArtificial SequenceSynthetic 22Gly Phe Thr Phe Ser Ser Tyr Trp1
52324DNAArtificial SequenceSynthetic 23ataaaacaag atggaagtga
gaaa 24248PRTArtificial
SequenceSynthetic 24Ile Lys Gln Asp Gly Ser Glu Lys1
52554DNAArtificial SequenceSynthetic 25gcgagagatt ggaactatgg ccccgattac
tactactacc acggtttgga cgtc 542618PRTArtificial
SequenceSynthetic 26Ala Arg Asp Trp Asn Tyr Gly Pro Asp Tyr Tyr Tyr Tyr
His Gly Leu1 5 10 15Asp
Val27322DNAArtificial SequenceSynthetic 27gacctccaga tgacccagtc
tccgtcctcc ctgtctgtat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca
gggcattaga aatgatttag gctggtttca gcagaaacca 120gggaaagccc ctaagcgcct
gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc
tgggacagaa ttcactctca caatcagcag cctgctgcct 240gaagattttg caacttatta
ctgtctacag cataatactt acccgtacac ttttggccag 300gggaccaagc tggagatcaa
ac 32228107PRTArtificial
SequenceSynthetic 28Asp Leu Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Val
Ser Val Gly1 5 10 15Asp
Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp20
25 30Leu Gly Trp Phe Gln Gln Lys Pro Gly Lys Ala
Pro Lys Arg Leu Ile35 40 45Tyr Ala Ala
Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly50 55
60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser
Leu Leu Pro65 70 75
80Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Thr Tyr Pro Tyr85
90 95Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
Lys100 1052918DNAArtificial SequenceSynthetic
29cagggcatta gaaatgat
18306PRTArtificial SequenceSynthetic 30Gln Gly Ile Arg Asn Asp1
5319DNAArtificial SequenceSynthetic 31gctgcatcc
9323PRTArtificial
SequenceSynthetic 32Ala Ala Ser13327DNAArtificial SequenceSynthetic
33ctacagcata atacttaccc gtacact
27349PRTArtificial SequenceSynthetic 34Leu Gln His Asn Thr Tyr Pro Tyr
Thr1 535361DNAArtificial SequenceSynthetic 35caggggcagt
tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgaag
catctggatt cagtttcaga agttatggca tgcactgggt ccgccaggct 120ccaggcaggg
gactggagtg gatggcagtt atttggtacg atggcagtaa gacatactat 180acagagtccg
tgacgggccg attcaccatc tccagagaca attccaagaa cacgctatat 240ctgcaaatga
acagcctgag agccgaggac acggctgttt attactgtgc gagcggtttt 300tcagtgcctg
ccacgatcct tgacaactgg ggccagggaa ccctggtctc cgtctcctca 360g
36136120PRTArtificial SequenceSynthetic 36Gln Gly Gln Leu Val Glu Ser Gly
Gly Gly Val Val Gln Pro Gly Arg1 5 10
15Ser Leu Arg Leu Ser Cys Glu Ala Ser Gly Phe Ser Phe Arg Ser
Tyr20 25 30Gly Met His Trp Val Arg Gln
Ala Pro Gly Arg Gly Leu Glu Trp Met35 40
45Ala Val Ile Trp Tyr Asp Gly Ser Lys Thr Tyr Tyr Thr Glu Ser Val50
55 60Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys85 90 95Ala Ser Gly Phe Ser Val Pro
Ala Thr Ile Leu Asp Asn Trp Gly Gln100 105
110Gly Thr Leu Val Ser Val Ser Ser115
1203724DNAArtificial SequenceSynthetic 37ggattcagtt tcagaagtta tggc
24388PRTArtificial SequenceSynthetic
38Gly Phe Ser Phe Arg Ser Tyr Gly1 53924DNAArtificial
SequenceSynthetic 39atttggtacg atggcagtaa gaca
24408PRTArtificial SequenceSynthetic 40Ile Trp Tyr Asp
Gly Ser Lys Thr1 54139DNAArtificial SequenceSynthetic
41gcgagcggtt tttcagtgcc tgccacgatc cttgacaac
394213PRTArtificial SequenceSynthetic 42Ala Ser Gly Phe Ser Val Pro Ala
Thr Ile Leu Asp Asn1 5
1043322DNAArtificial SequenceSynthetic 43gacatccaga tgacccagtc tccatcctcc
ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcattaga
aatgatttag gctggtttca gcagaaacca 120gggaaagccc ctaaccgcct gatctatgga
gcatccagtt tggaaggtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat
ttcactctca caatcagcag cctgcagcca 240gaagattttg caacttatta ctgtctacag
cataattctt acccgtggac gttcggccaa 300gggaccaagg tggaaatcaa ac
32244107PRTArtificial SequenceSynthetic
44Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1
5 10 15Asp Arg Val Thr Ile Thr
Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp20 25
30Leu Gly Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Asn Arg Leu Ile35
40 45Tyr Gly Ala Ser Ser Leu Glu Gly Gly
Val Pro Ser Arg Phe Ser Gly50 55 60Ser
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65
70 75 80Glu Asp Phe Ala Thr Tyr
Tyr Cys Leu Gln His Asn Ser Tyr Pro Trp85 90
95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys100
1054518DNAArtificial SequenceSynthetic 45cagggcatta gaaatgat
18466PRTArtificial SequenceSynthetic
46Gln Gly Ile Arg Asn Asp1 5479DNAArtificial
SequenceSynthetic 47ggagcatcc
9483PRTArtificial SequenceSynthetic 48Gly Ala
Ser14927DNAArtificial SequenceSynthetic 49ctacagcata attcttaccc gtggacg
27509PRTArtificial
SequenceSynthetic 50Leu Gln His Asn Ser Tyr Pro Trp Thr1
551367DNAArtificial SequenceSynthetic 51caggtgcagc tggtggagtc tgggggaggc
gtagtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt
agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt
atatggtatg atggaaataa taaatactat 180atagactccg tgaagggccg attcaccatc
tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac
acggctgtgt attactgtgc gagagaccgt 300ggatatagtg gctacgaggg atacttcgat
ctctggggcc gtggcaccct ggtcactgtc 360tcctcag
36752122PRTArtificial SequenceSynthetic
52Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1
5 10 15Ser Leu Arg Leu Ser Cys
Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr20 25
30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val35
40 45Ala Val Ile Trp Tyr Asp Gly Asn Asn
Lys Tyr Tyr Ile Asp Ser Val50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys85 90
95Ala Arg Asp Arg Gly Tyr Ser Gly Tyr Glu Gly Tyr Phe Asp Leu Trp100
105 110Gly Arg Gly Thr Leu Val Thr Val
Ser Ser115 1205324DNAArtificial SequenceSynthetic
53ggattcacct tcagtagcta tggc
24548PRTArtificial SequenceSynthetic 54Gly Phe Thr Phe Ser Ser Tyr Gly1
55524DNAArtificial SequenceSynthetic 55atatggtatg atggaaataa
taaa 24568PRTArtificial
SequenceSynthetic 56Ile Trp Tyr Asp Gly Asn Asn Lys1
55745DNAArtificial SequenceSynthetic 57gcgagagacc gtggatatag tggctacgag
ggatacttcg atctc 455815PRTArtificial
SequenceSynthetic 58Ala Arg Asp Arg Gly Tyr Ser Gly Tyr Glu Gly Tyr Phe
Asp Leu1 5 10
1559337DNAArtificial SequenceSynthetic 59gacatcgtga tgacccagtc tccagactcc
ctggctgtgt ctctgggcga gagggccacc 60ctcaactgta agtccagcca gagtgtttta
tacagctcca acaataagaa ctacttagct 120tggtaccagc agaaaccagg acagcctcct
aagctgctca tttactgggc atctacccgg 180gaatccgggg tccctgaccg attcagtggc
agcgggtctg ggacagattt cactctcacc 240atcagcagcc tgcaggctga agatgtggca
gtttatttct gtcagcaata ttatactact 300tggacgttcg gccaagggac caaggtggaa
atcaaac 33760112PRTArtificial
SequenceSynthetic 60Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val
Ser Leu Gly1 5 10 15Glu
Arg Ala Thr Leu Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser20
25 30Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln
Gln Lys Pro Gly Gln35 40 45Pro Pro Lys
Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val50 55
60Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
Thr Leu Thr65 70 75
80Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Phe Cys Gln Gln85
90 95Tyr Tyr Thr Thr Trp Thr Phe Gly Gln Gly
Thr Lys Val Glu Ile Lys100 105
1106136DNAArtificial SequenceSynthetic 61cagagtgttt tatacagctc caacaataag
aactac 366212PRTArtificial
SequenceSynthetic 62Gln Ser Val Leu Tyr Ser Ser Asn Asn Lys Asn Tyr1
5 10639DNAArtificial SequenceSynthetic
63tgggcatct
9643PRTArtificial SequenceSynthetic 64Trp Ala Ser16524DNAArtificial
SequenceSynthetic 65cagcaatatt atactacttg gacg
24668PRTArtificial SequenceSynthetic 66Gln Gln Tyr Tyr
Thr Thr Trp Thr1 567385DNAArtificial SequenceSynthetic
67caggtgcagt tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc
60tcctgtgcag cctctgcatc caccttcagt aggcatggca tgcactgggt ccgccaggct
120ccaggcaagg gactggagtg ggtggcagtt atatcatatg atggaaataa taaatactat
180gtagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat
240ctgcaaatga atagcctgag aactgacgac acggctgtgt attattgttc gaaagagtta
300gtaggtatta ctggaaacct ggtctactac tactactacg gaatggacgt ctggggccaa
360gggaccacgg tcaccgtctc ctcag
38568128PRTArtificial SequenceSynthetic 68Gln Val Gln Leu Val Glu Ser Gly
Gly Gly Val Val Gln Pro Gly Arg1 5 10
15Ser Leu Arg Leu Ser Cys Ala Ala Ser Ala Ser Thr Phe Ser Arg
His20 25 30Gly Met His Trp Val Arg Gln
Ala Pro Gly Lys Gly Leu Glu Trp Val35 40
45Ala Val Ile Ser Tyr Asp Gly Asn Asn Lys Tyr Tyr Val Asp Ser Val50
55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Thr Asp Asp Thr Ala Val Tyr Tyr
Cys85 90 95Ser Lys Glu Leu Val Gly Ile
Thr Gly Asn Leu Val Tyr Tyr Tyr Tyr100 105
110Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser115
120 1256924DNAArtificial SequenceSynthetic
69gcatccacct tcagtaggca tggc
24708PRTArtificial SequenceSynthetic 70Ala Ser Thr Phe Ser Arg His Gly1
57124DNAArtificial SequenceSynthetic 71atatcatatg atggaaataa
taaa 24728PRTArtificial
SequenceSynthetic 72Ile Ser Tyr Asp Gly Asn Asn Lys1
57363DNAArtificial SequenceSynthetic 73tcgaaagagt tagtaggtat tactggaaac
ctggtctact actactacta cggaatggac 60gtc
637421PRTArtificial SequenceSynthetic
74Ser Lys Glu Leu Val Gly Ile Thr Gly Asn Leu Val Tyr Tyr Tyr Tyr1
5 10 15Tyr Gly Met Asp
Val2075325DNAArtificial SequenceSynthetic 75gaaattgtgt tgacgcagtc
tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca
gactattaac agcagctact taggctggta ccagcagaaa 120cctggccagg ctcccagact
cctcatctat ggtgcatcca acagggccac tggcatccca 180gacagtttca gtggcagtgg
gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtgta
ttactgtcaa cattataaca actcacctta cacttttggc 300caggggacca agctggagat
caaac 32576108PRTArtificial
SequenceSynthetic 76Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu
Ser Pro Gly1 5 10 15Glu
Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Thr Ile Asn Ser Ser20
25 30Tyr Leu Gly Trp Tyr Gln Gln Lys Pro Gly Gln
Ala Pro Arg Leu Leu35 40 45Ile Tyr Gly
Ala Ser Asn Arg Ala Thr Gly Ile Pro Asp Ser Phe Ser50 55
60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
Arg Leu Glu65 70 75
80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Asn Asn Ser Pro85
90 95Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu
Ile Lys100 1057721DNAArtificial SequenceSynthetic
77cagactatta acagcagcta c
21787PRTArtificial SequenceSynthetic 78Gln Thr Ile Asn Ser Ser Tyr1
5799DNAArtificial SequenceSynthetic 79ggtgcatcc
9803PRTArtificial
SequenceSynthetic 80Gly Ala Ser18127DNAArtificial SequenceSynthetic
81caacattata acaactcacc ttacact
27829PRTArtificial SequenceSynthetic 82Gln His Tyr Asn Asn Ser Pro Tyr
Thr1 583361DNAArtificial SequenceSynthetic 83caggtgcagc
tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg
tctctggtgg ctccataagc agtggtggtt actactggag ctggatccgc 120cactacccag
ggaagggcct ggagtggatt ggctacgtcc attacagtgg gaacacccac 180tacaatacgt
ccctcaagag gcgacttacc atatcaatag acacgtctaa gagccaattc 240tccctggatc
tgagctctgt gactgccgcg gacacggccg tgtattactg tgcgagagcc 300ccccgtggat
accattactt tgcctactgg ggccagggaa ccctggtcac cgtctcctca 360g
36184120PRTArtificial SequenceSynthetic 84Gln Val Gln Leu Gln Glu Ser Gly
Pro Gly Leu Val Lys Pro Ser Gln1 5 10
15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser
Gly20 25 30Gly Tyr Tyr Trp Ser Trp Ile
Arg His Tyr Pro Gly Lys Gly Leu Glu35 40
45Trp Ile Gly Tyr Val His Tyr Ser Gly Asn Thr His Tyr Asn Thr Ser50
55 60Leu Lys Arg Arg Leu Thr Ile Ser Ile Asp
Thr Ser Lys Ser Gln Phe65 70 75
80Ser Leu Asp Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr
Tyr85 90 95Cys Ala Arg Ala Pro Arg Gly
Tyr His Tyr Phe Ala Tyr Trp Gly Gln100 105
110Gly Thr Leu Val Thr Val Ser Ser115
1208530DNAArtificial SequenceSynthetic 85ggtggctcca taagcagtgg tggttactac
308610PRTArtificial
SequenceSynthetic 86Gly Gly Ser Ile Ser Ser Gly Gly Tyr Tyr1
5 108721DNAArtificial SequenceSynthetic 87gtccattaca
gtgggaacac c
21887PRTArtificial SequenceSynthetic 88Val His Tyr Ser Gly Asn Thr1
58936DNAArtificial SequenceSynthetic 89gcgagagccc cccgtggata
ccattacttt gcctac 369012PRTArtificial
SequenceSynthetic 90Ala Arg Ala Pro Arg Gly Tyr His Tyr Phe Ala Tyr1
5 1091325DNAArtificial SequenceSynthetic
91gaaattgggt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc
60ctctcctgca gggccagtca gagtattagc agcaggtact tagcctggta ccagcagaaa
120cctggccagg ctcccaggct cctcatcttt ggtgcatcca gcagggccac tggcatacca
180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag
240cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcaccgct cactttcggc
300ggagggacca aggtggagat caaac
32592108PRTArtificial SequenceSynthetic 92Glu Ile Gly Leu Thr Gln Ser Pro
Gly Thr Leu Ser Leu Ser Pro Gly1 5 10
15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Ser
Arg20 25 30Tyr Leu Ala Trp Tyr Gln Gln
Lys Pro Gly Gln Ala Pro Arg Leu Leu35 40
45Ile Phe Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser50
55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile Ser Arg Leu Glu65 70 75
80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser
Pro85 90 95Leu Thr Phe Gly Gly Gly Thr
Lys Val Glu Ile Lys100 1059321DNAArtificial
SequenceSynthetic 93cagagtatta gcagcaggta c
21947PRTArtificial SequenceSynthetic 94Gln Ser Ile Ser
Ser Arg Tyr1 5959DNAArtificial SequenceSynthetic
95ggtgcatcc
9963PRTArtificial SequenceSynthetic 96Gly Ala Ser19727DNAArtificial
SequenceSynthetic 97cagcagtatg gtagctcacc gctcact
27989PRTArtificial SequenceSynthetic 98Gln Gln Tyr Gly
Ser Ser Pro Leu Thr1 599361DNAArtificial SequenceSynthetic
99caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc
60acctgcactg tctctggtgg ctccatcagc agtagtggtt actactggag ttggatccgc
120cagcacccag ggaagggcct ggagtggatt gggtacgtcc attacagtgg gaacacccac
180tacagcccgt ccctcaagag tcgacttacc atatcagttg acacgtctaa gaaccagttc
240tccctgaagc tgagctctgt gactgccgcg gacacggccg tgtattactg tgcgagagcc
300ccccgtggat accattactt tgcctactgg ggccagggaa ccctggtcac cgtctcctca
360g
361100120PRTArtificial SequenceSynthetic 100Gln Val Gln Leu Gln Glu Ser
Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10
15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser
Ser Ser20 25 30Gly Tyr Tyr Trp Ser Trp
Ile Arg Gln His Pro Gly Lys Gly Leu Glu35 40
45Trp Ile Gly Tyr Val His Tyr Ser Gly Asn Thr His Tyr Ser Pro Ser50
55 60Leu Lys Ser Arg Leu Thr Ile Ser Val
Asp Thr Ser Lys Asn Gln Phe65 70 75
80Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val
Tyr Tyr85 90 95Cys Ala Arg Ala Pro Arg
Gly Tyr His Tyr Phe Ala Tyr Trp Gly Gln100 105
110Gly Thr Leu Val Thr Val Ser Ser115
12010130DNAArtificial SequenceSynthetic 101ggtggctcca tcagcagtag
tggttactac 3010210PRTArtificial
SequenceSynthetic 102Gly Gly Ser Ile Ser Ser Ser Gly Tyr Tyr1
5 1010321DNAArtificial SequenceSynthetic 103gtccattaca
gtgggaacac c
211047PRTArtificial SequenceSynthetic 104Val His Tyr Ser Gly Asn Thr1
510536DNAArtificial SequenceSynthetic 105gcgagagccc cccgtggata
ccattacttt gcctac 3610612PRTArtificial
SequenceSynthetic 106Ala Arg Ala Pro Arg Gly Tyr His Tyr Phe Ala Tyr1
5 10107325DNAArtificial SequenceSynthetic
107aaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga gagagccacc
60ctctcctgca gggccagtca gagtattagc agcagctact tagcctggta ccagcagaaa
120cctggccagg ctcccaggct cctcatcttt ggtgcatcca gcagggccac tggcatccca
180gacaggttca gtggcagtgg gtctgggcca gacttcactc tcaccattag gagactggag
240cctgaagatt ttgcggtgta ttactgtcag cagtatggta gttcaccgct cactttcggc
300ggagggacca aggtggagat caaac
325108108PRTArtificial SequenceSynthetic 108Lys Ile Val Leu Thr Gln Ser
Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10
15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser
Ser Ser20 25 30Tyr Leu Ala Trp Tyr Gln
Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu35 40
45Ile Phe Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser50
55 60Gly Ser Gly Ser Gly Pro Asp Phe Thr
Leu Thr Ile Arg Arg Leu Glu65 70 75
80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser
Ser Pro85 90 95Leu Thr Phe Gly Gly Gly
Thr Lys Val Glu Ile Lys100 10510921DNAArtificial
SequenceSynthetic 109cagagtatta gcagcagcta c
211107PRTArtificial SequenceSynthetic 110Gln Ser Ile Ser
Ser Ser Tyr1 51119DNAArtificial SequenceSynthetic
111ggtgcatcc
91123PRTArtificial SequenceSynthetic 112Gly Ala Ser111327DNAArtificial
SequenceSynthetic 113cagcagtatg gtagttcacc gctcact
271149PRTArtificial SequenceSynthetic 114Gln Gln Tyr Gly
Ser Ser Pro Leu Thr1 5115358DNAArtificial SequenceSynthetic
115caggttcagt tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc
60tcctgcaagg cttctggtta caccttttcc acctatggta tcagctgggt gcgacaggcc
120cctggacaag ggcttgagtg gatgggatgg atcagcgctt acgacaataa cgcggactat
180gcacagaact tccaggccag agtcaccatg accacagaca catccacgac cacagcctac
240atggagctga ggagcctgag atctgacgac acggccgtgt attactgtgc gaggtatagc
300tggaactttc actggttcga cccctggggc cagggaaccc tggtcaccgt ctcctcag
358116119PRTArtificial SequenceSynthetic 116Gln Val Gln Leu Val Gln Ser
Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10
15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser
Thr Tyr20 25 30Gly Ile Ser Trp Val Arg
Gln Ala Pro Gly Gln Gly Leu Glu Trp Met35 40
45Gly Trp Ile Ser Ala Tyr Asp Asn Asn Ala Asp Tyr Ala Gln Asn Phe50
55 60Gln Ala Arg Val Thr Met Thr Thr Asp
Thr Ser Thr Thr Thr Ala Tyr65 70 75
80Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr
Tyr Cys85 90 95Ala Arg Tyr Ser Trp Asn
Phe His Trp Phe Asp Pro Trp Gly Gln Gly100 105
110Thr Leu Val Thr Val Ser Ser11511724DNAArtificial
SequenceSynthetic 117ggttacacct tttccaccta tggt
241188PRTArtificial SequenceSynthetic 118Gly Tyr Thr Phe
Ser Thr Tyr Gly1 511924DNAArtificial SequenceSynthetic
119atcagcgctt acgacaataa cgcg
241208PRTArtificial SequenceSynthetic 120Ile Ser Ala Tyr Asp Asn Asn Ala1
512136DNAArtificial SequenceSynthetic 121gcgaggtata
gctggaactt tcactggttc gacccc
3612212PRTArtificial SequenceSynthetic 122Ala Arg Tyr Ser Trp Asn Phe His
Trp Phe Asp Pro1 5 10123325DNAArtificial
SequenceSynthetic 123gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt
ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agtacctact
tagcctggta ccagcagcaa 120cctggccagg ctcccaggct cctcatctat ggtgcatcca
gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc
tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcag cagtatggta
actcaccgtg gacgttcggc 300caagggacca aggtggaaat caaac
325124108PRTArtificial SequenceSynthetic 124Glu
Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1
5 10 15Glu Arg Ala Thr Leu Ser Cys Arg
Ala Ser Gln Ser Val Ser Ser Thr20 25
30Tyr Leu Ala Trp Tyr Gln Gln Gln Pro Gly Gln Ala Pro Arg Leu Leu35
40 45Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly
Ile Pro Asp Arg Phe Ser50 55 60Gly Ser
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65
70 75 80Pro Glu Asp Phe Ala Val Tyr
Tyr Cys Gln Gln Tyr Gly Asn Ser Pro85 90
95Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys100
10512521DNAArtificial SequenceSynthetic 125cagagtgtta gcagtaccta c
211267PRTArtificial
SequenceSynthetic 126Gln Ser Val Ser Ser Thr Tyr1
51279DNAArtificial SequenceSynthetic 127ggtgcatcc
91283PRTArtificial SequenceSynthetic
128Gly Ala Ser112927DNAArtificial SequenceSynthetic 129cagcagtatg
gtaactcacc gtggacg
271309PRTArtificial SequenceSynthetic 130Gln Gln Tyr Gly Asn Ser Pro Trp
Thr1 5131358DNAArtificial SequenceSynthetic 131caggttcacc
tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaggg
cttctggtta cacctttacc aactatggta tcacctgggt gcgacaggcc 120cctggacaag
ggcttgagtg gatgggatgg atcagcgctt acagtggtaa cacagactat 180gcacagaagt
tccaggccag aatcaccatg accacagaca catccacgac cacagcctac 240atggaactga
ggagcctgac atctgacgac acggccgtgt attactgtgc gaggtatagc 300tggaactttc
actggttcga cccctggggc cagggaaccc tggtcaccgt ctcctcag
358132119PRTArtificial SequenceSynthetic 132Gln Val His Leu Val Gln Ser
Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10
15Ser Val Lys Val Ser Cys Arg Ala Ser Gly Tyr Thr Phe Thr
Asn Tyr20 25 30Gly Ile Thr Trp Val Arg
Gln Ala Pro Gly Gln Gly Leu Glu Trp Met35 40
45Gly Trp Ile Ser Ala Tyr Ser Gly Asn Thr Asp Tyr Ala Gln Lys Phe50
55 60Gln Ala Arg Ile Thr Met Thr Thr Asp
Thr Ser Thr Thr Thr Ala Tyr65 70 75
80Met Glu Leu Arg Ser Leu Thr Ser Asp Asp Thr Ala Val Tyr
Tyr Cys85 90 95Ala Arg Tyr Ser Trp Asn
Phe His Trp Phe Asp Pro Trp Gly Gln Gly100 105
110Thr Leu Val Thr Val Ser Ser11513324DNAArtificial
SequenceSynthetic 133ggttacacct ttaccaacta tggt
241348PRTArtificial SequenceSynthetic 134Gly Tyr Thr Phe
Thr Asn Tyr Gly1 513524DNAArtificial SequenceSynthetic
135atcagcgctt acagtggtaa caca
241368PRTArtificial SequenceSynthetic 136Ile Ser Ala Tyr Ser Gly Asn Thr1
513736DNAArtificial SequenceSynthetic 137gcgaggtata
gctggaactt tcactggttc gacccc
3613812PRTArtificial SequenceSynthetic 138Ala Arg Tyr Ser Trp Asn Phe His
Trp Phe Asp Pro1 5 10139325DNAArtificial
SequenceSynthetic 139gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt
ctccagggga cagagtcacc 60ctctcctgca gggccagtca gagtgttagt agcagctact
tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctat ggtgcatcca
gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc
tcaccatcag cagtctggag 240cctgaagatt ttgcagtgta ttactgtcag cagtgtggtg
gctcaccgtg gacgttcggc 300caagggacca gggtggagat caaac
325140108PRTArtificial SequenceSynthetic 140Glu
Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1
5 10 15Asp Arg Val Thr Leu Ser Cys Arg
Ala Ser Gln Ser Val Ser Ser Ser20 25
30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu35
40 45Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly
Ile Pro Asp Arg Phe Ser50 55 60Gly Ser
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu65
70 75 80Pro Glu Asp Phe Ala Val Tyr
Tyr Cys Gln Gln Cys Gly Gly Ser Pro85 90
95Trp Thr Phe Gly Gln Gly Thr Arg Val Glu Ile Lys100
10514121DNAArtificial SequenceSynthetic 141cagagtgtta gtagcagcta c
211427PRTArtificial
SequenceSynthetic 142Gln Ser Val Ser Ser Ser Tyr1
51439DNAArtificial SequenceSynthetic 143ggtgcatcc
91443PRTArtificial SequenceSynthetic
144Gly Ala Ser114527DNAArtificial SequenceSynthetic 145cagcagtgtg
gtggctcacc gtggacg
271469PRTArtificial SequenceSynthetic 146Gln Gln Cys Gly Gly Ser Pro Trp
Thr1 5147358DNAArtificial SequenceSynthetic 147caggttcaac
tggtgcagtc tgggcctgag gtgaagaagc ctggggcctc agtgaaggtc 60gcctgcaagg
cttctggtta cacctttacc cactatggtt tcacctgggt gcgacaggcc 120cctggacaag
ggcttgagtg gatgggatgg atcagcgctt acagtggtca tacagactat 180gcacggaagt
tccaggccag agtcaccatg accacagaca cattcacgac cacagcctac 240atggaactga
ggagcctgag atctgacgac acggccgttt attactgtgc gagttatagc 300tggaactttc
actggttcga cccctggggc cagggaaccc tggtcaccgt ctcctcag
358148119PRTArtificial SequenceSynthetic 148Gln Val Gln Leu Val Gln Ser
Gly Pro Glu Val Lys Lys Pro Gly Ala1 5 10
15Ser Val Lys Val Ala Cys Lys Ala Ser Gly Tyr Thr Phe Thr
His Tyr20 25 30Gly Phe Thr Trp Val Arg
Gln Ala Pro Gly Gln Gly Leu Glu Trp Met35 40
45Gly Trp Ile Ser Ala Tyr Ser Gly His Thr Asp Tyr Ala Arg Lys Phe50
55 60Gln Ala Arg Val Thr Met Thr Thr Asp
Thr Phe Thr Thr Thr Ala Tyr65 70 75
80Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr
Tyr Cys85 90 95Ala Ser Tyr Ser Trp Asn
Phe His Trp Phe Asp Pro Trp Gly Gln Gly100 105
110Thr Leu Val Thr Val Ser Ser11514924DNAArtificial
SequenceSynthetic 149ggttacacct ttacccacta tggt
241508PRTArtificial SequenceSynthetic 150Gly Tyr Thr Phe
Thr His Tyr Gly1 515124DNAArtificial SequenceSynthetic
151atcagcgctt acagtggtca taca
241528PRTArtificial SequenceSynthetic 152Ile Ser Ala Tyr Ser Gly His Thr1
515336DNAArtificial SequenceSynthetic 153gcgagttata
gctggaactt tcactggttc gacccc
3615412PRTArtificial SequenceSynthetic 154Ala Ser Tyr Ser Trp Asn Phe His
Trp Phe Asp Pro1 5 10155325DNAArtificial
SequenceSynthetic 155caaattgtgt tgacgcagtc tccaggcacc ctgtctttgt
ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagt accacctact
tagcctggta ccagcagaaa 120cctggccagg ctcccagtct cctcatctat ggtacatcca
ccagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggact gacttcactc
tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcag cagtgtggtg
gctcaccgtg gacgttcggc 300caagggacca aggtgaaaat caaac
325156108PRTArtificial SequenceSynthetic 156Gln
Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1
5 10 15Glu Arg Ala Thr Leu Ser Cys Arg
Ala Ser Gln Ser Val Ser Thr Thr20 25
30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ser Leu Leu35
40 45Ile Tyr Gly Thr Ser Thr Arg Ala Thr Gly
Ile Pro Asp Arg Phe Ser50 55 60Gly Ser
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65
70 75 80Pro Glu Asp Phe Ala Val Tyr
Tyr Cys Gln Gln Cys Gly Gly Ser Pro85 90
95Trp Thr Phe Gly Gln Gly Thr Lys Val Lys Ile Lys100
10515721DNAArtificial SequenceSynthetic 157cagagtgtta gtaccaccta c
211587PRTArtificial
SequenceSynthetic 158Gln Ser Val Ser Thr Thr Tyr1
51599DNAArtificial SequenceSynthetic 159ggtacatcc
91603PRTArtificial SequenceSynthetic
160Gly Thr Ser116127DNAArtificial SequenceSynthetic 161cagcagtgtg
gtggctcacc gtggacg
271629PRTArtificial SequenceSynthetic 162Gln Gln Cys Gly Gly Ser Pro Trp
Thr1 5163367DNAArtificial SequenceSynthetic 163caggtgcagt
tggtgcagtc tggggctgag gtgaagaagc ctggggccgc tgtgaaggtc 60tcctgcaagg
cttctggata cacgttcacc agttatgata tcaactgggt gcgacaggcc 120actggacaag
ggcttgagtg gatgggatgg ataaacccta acagtggtaa cacaggctat 180gcacagaagt
ttcagggcag agtcaccttg accaggaaca cctccataag cacagcctac 240atggaactga
gcagcctgag atctgaggac acggccgttt attactgtgc gagagaggga 300tattgtggtg
gtgattgcta tgcttttgat atctggggcc aagggacaat ggtcaccgtc 360tcttcag
367164122PRTArtificial SequenceSynthetic 164Gln Val Gln Leu Val Gln Ser
Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10
15Ala Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
Ser Tyr20 25 30Asp Ile Asn Trp Val Arg
Gln Ala Thr Gly Gln Gly Leu Glu Trp Met35 40
45Gly Trp Ile Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala Gln Lys Phe50
55 60Gln Gly Arg Val Thr Leu Thr Arg Asn
Thr Ser Ile Ser Thr Ala Tyr65 70 75
80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr
Tyr Cys85 90 95Ala Arg Glu Gly Tyr Cys
Gly Gly Asp Cys Tyr Ala Phe Asp Ile Trp100 105
110Gly Gln Gly Thr Met Val Thr Val Ser Ser115
12016524DNAArtificial SequenceSynthetic 165ggatacacgt tcaccagtta tgat
241668PRTArtificial
SequenceSynthetic 166Gly Tyr Thr Phe Thr Ser Tyr Asp1
516724DNAArtificial SequenceSynthetic 167ataaacccta acagtggtaa caca
241688PRTArtificial
SequenceSynthetic 168Ile Asn Pro Asn Ser Gly Asn Thr1
516945DNAArtificial SequenceSynthetic 169gcgagagagg gatattgtgg tggtgattgc
tatgcttttg atatc 4517015PRTArtificial
SequenceSynthetic 170Ala Arg Glu Gly Tyr Cys Gly Gly Asp Cys Tyr Ala Phe
Asp Ile1 5 10
15171325DNAArtificial SequenceSynthetic 171gaaattgtgt tgacacaatc
tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca
gagtgttagc agcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct
cctcatcttt ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg
gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtgta
ttactgtcag cagtatggta gctcaccgct cactttcggc 300ggagggacca aggtggagat
caaac 325172108PRTArtificial
SequenceSynthetic 172Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu
Ser Pro Gly1 5 10 15Glu
Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser20
25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
Ala Pro Arg Leu Leu35 40 45Ile Phe Gly
Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser50 55
60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
Arg Leu Glu65 70 75
80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro85
90 95Leu Thr Phe Gly Gly Gly Thr Lys Val Glu
Ile Lys100 10517321DNAArtificial SequenceSynthetic
173cagagtgtta gcagcagcta c
211747PRTArtificial SequenceSynthetic 174Gln Ser Val Ser Ser Ser Tyr1
51759DNAArtificial SequenceSynthetic 175ggtgcatcc
91763PRTArtificial
SequenceSynthetic 176Gly Ala Ser117727DNAArtificial SequenceSynthetic
177cagcagtatg gtagctcacc gctcact
271789PRTArtificial SequenceSynthetic 178Gln Gln Tyr Gly Ser Ser Pro Leu
Thr1 5179361DNAArtificial SequenceSynthetic 179cagctgcagc
tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60acctgcactg
tctctggtgg ctccatcagc agtagtagtt actactgggg ctggatccgc 120cagcccccag
ggaaggggct ggagtggatt gggagtatct attatagtgg gagcacctac 180tacaacccgt
ccctcaagag tcgagtcacc atatccgtag acacgtccaa gaaccagttc 240tccctgaagc
tgagctctgt gaccgccgca gacacggctg tgtattactg tgcggcaaac 300tgggacgacg
ccttcttctt tgactactgg ggccagggaa ccctggtcac cgtctcctca 360g
361180120PRTArtificial SequenceSynthetic 180Gln Leu Gln Leu Gln Glu Ser
Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10
15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser
Ser Ser20 25 30Ser Tyr Tyr Trp Gly Trp
Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu35 40
45Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser50
55 60Leu Lys Ser Arg Val Thr Ile Ser Val
Asp Thr Ser Lys Asn Gln Phe65 70 75
80Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val
Tyr Tyr85 90 95Cys Ala Ala Asn Trp Asp
Asp Ala Phe Phe Phe Asp Tyr Trp Gly Gln100 105
110Gly Thr Leu Val Thr Val Ser Ser115
12018130DNAArtificial SequenceSynthetic 181ggtggctcca tcagcagtag
tagttactac 3018210PRTArtificial
SequenceSynthetic 182Gly Gly Ser Ile Ser Ser Ser Ser Tyr Tyr1
5 1018321DNAArtificial SequenceSynthetic 183atctattata
gtgggagcac c
211847PRTArtificial SequenceSynthetic 184Ile Tyr Tyr Ser Gly Ser Thr1
518536DNAArtificial SequenceSynthetic 185gcggcaaact gggacgacgc
cttcttcttt gactac 3618612PRTArtificial
SequenceSynthetic 186Ala Ala Asn Trp Asp Asp Ala Phe Phe Phe Asp Tyr1
5 10187322DNAArtificial SequenceSynthetic
187gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc
60atcacttgcc gggccagtca gagtattagt agctggttgg cctggtatca gcagaaacca
120gggaaagccc ctaagctcct gatctataag gcgtctagtt tagaaagtgg ggtcccatca
180aggttcagcg gcagtggatc tgggacagaa ttcactctca ccatcagcag cctgcagcct
240gatgattttg caacttatta ctgccaacag tataatagtt attcgtacac ttttggccag
300gggaccaagc tggagatcaa ac
322188107PRTArtificial SequenceSynthetic 188Asp Ile Gln Met Thr Gln Ser
Pro Ser Thr Leu Ser Ala Ser Val Gly1 5 10
15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser
Ser Trp20 25 30Leu Ala Trp Tyr Gln Gln
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile35 40
45Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly50
55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro65 70 75
80Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr
Ser Tyr85 90 95Thr Phe Gly Gln Gly Thr
Lys Leu Glu Ile Lys100 10518918DNAArtificial
SequenceSynthetic 189cagagtatta gtagctgg
181906PRTArtificial SequenceSynthetic 190Gln Ser Ile Ser
Ser Trp1 51919DNAArtificial SequenceSynthetic 191aaggcgtct
91923PRTArtificial SequenceSynthetic 192Lys Ala Ser119327DNAArtificial
SequenceSynthetic 193caacagtata atagttattc gtacact
271949PRTArtificial SequenceSynthetic 194Gln Gln Tyr Asn
Ser Tyr Ser Tyr Thr1 5195352DNAArtificial SequenceSynthetic
195caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc
60tcctgcaagg cttctggata caccttcacc ggctactata ttcactgggt acgacaggcc
120cctggacaag gccttgagtg gatgggatgg atcaacccta acagtggtgg cacaaactat
180gcacagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcac cacagcctac
240atggagctga gcaggctgat atctgacgac acggccgtgt attactgtgc gagaggaccc
300tgggatttct ttgactactg gggccaggga accctggtca ccgtctcctc ag
352196117PRTArtificial SequenceSynthetic 196Gln Val Gln Leu Val Gln Ser
Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10
15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
Gly Tyr20 25 30Tyr Ile His Trp Val Arg
Gln Ala Pro Gly Gln Gly Leu Glu Trp Met35 40
45Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe50
55 60Gln Gly Arg Val Thr Met Thr Arg Asp
Thr Ser Ile Thr Thr Ala Tyr65 70 75
80Met Glu Leu Ser Arg Leu Ile Ser Asp Asp Thr Ala Val Tyr
Tyr Cys85 90 95Ala Arg Gly Pro Trp Asp
Phe Phe Asp Tyr Trp Gly Gln Gly Thr Leu100 105
110Val Thr Val Ser Ser11519724DNAArtificial SequenceSynthetic
197ggatacacct tcaccggcta ctat
241988PRTArtificial SequenceSynthetic 198Gly Tyr Thr Phe Thr Gly Tyr Tyr1
519924DNAArtificial SequenceSynthetic 199atcaacccta
acagtggtgg caca
242008PRTArtificial SequenceSynthetic 200Ile Asn Pro Asn Ser Gly Gly Thr1
520130DNAArtificial SequenceSynthetic 201gcgagaggac
cctgggattt ctttgactac
3020210PRTArtificial SequenceSynthetic 202Ala Arg Gly Pro Trp Asp Phe Phe
Asp Tyr1 5 10203340DNAArtificial
SequenceSynthetic 203gacatcgtga tgacccagtc tccagactcc ctggctgtgt
ctctgggcga gagggccacc 60atcaactgca agtccagcca gagtgtttta tacagctcca
acaataagaa ctacttagct 120tggtaccagc agaaaccagg acagcctcct aagctgctca
tttactgggc atctacccgg 180gaatccgggg tccctgaccg attcagtggc agcgggtctg
ggacagattt cactctcacc 240atcagcagcc tgcaggctga agatgtggca gtttattact
gtcagcaata ttatagtact 300ccgtacactt ttggccaggg gaccaagctg gagatcaaac
340204113PRTArtificial SequenceSynthetic 204Asp
Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly1
5 10 15Glu Arg Ala Thr Ile Asn Cys Lys
Ser Ser Gln Ser Val Leu Tyr Ser20 25
30Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln35
40 45Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser
Thr Arg Glu Ser Gly Val50 55 60Pro Asp
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr65
70 75 80Ile Ser Ser Leu Gln Ala Glu
Asp Val Ala Val Tyr Tyr Cys Gln Gln85 90
95Tyr Tyr Ser Thr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile100
105 110Lys20536DNAArtificial
SequenceSynthetic 205cagagtgttt tatacagctc caacaataag aactac
3620612PRTArtificial SequenceSynthetic 206Gln Ser Val
Leu Tyr Ser Ser Asn Asn Lys Asn Tyr1 5
102079DNAArtificial SequenceSynthetic 207tgggcatct
92083PRTArtificial
SequenceSynthetic 208Trp Ala Ser120927DNAArtificial SequenceSynthetic
209cagcaatatt atagtactcc gtacact
272109PRTArtificial SequenceSynthetic 210Gln Gln Tyr Tyr Ser Thr Pro Tyr
Thr1 5211352DNAArtificial SequenceSynthetic 211caggtgcagc
tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg
cttctggata caccttcacc ggctactata ttcactgggt acgacaggcc 120cctggacaag
gccttgagtg gatgggatgg atcaacccta acagtggtgg cacaaactat 180gcacagaagt
ttcagggcag ggtcaccatg accagggaca cgtccatcag cacagcctac 240atggagctga
gcaggctgag atctgacgac acggccgtgt attactgtgc gagaggaccc 300tgggatttct
ttgactactg gggccaggga accctggtca ccgtctcctc ag
352212117PRTArtificial SequenceSynthetic 212Gln Val Gln Leu Val Gln Ser
Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10
15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
Gly Tyr20 25 30Tyr Ile His Trp Val Arg
Gln Ala Pro Gly Gln Gly Leu Glu Trp Met35 40
45Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe50
55 60Gln Gly Arg Val Thr Met Thr Arg Asp
Thr Ser Ile Ser Thr Ala Tyr65 70 75
80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr
Tyr Cys85 90 95Ala Arg Gly Pro Trp Asp
Phe Phe Asp Tyr Trp Gly Gln Gly Thr Leu100 105
110Val Thr Val Ser Ser11521324DNAArtificial SequenceSynthetic
213ggatacacct tcaccggcta ctat
242148PRTArtificial SequenceSynthetic 214Gly Tyr Thr Phe Thr Gly Tyr Tyr1
521524DNAArtificial SequenceSynthetic 215atcaacccta
acagtggtgg caca
242168PRTArtificial SequenceSynthetic 216Ile Asn Pro Asn Ser Gly Gly Thr1
521730DNAArtificial SequenceSynthetic 217gcgagaggac
cctgggattt ctttgactac
3021810PRTArtificial SequenceSynthetic 218Ala Arg Gly Pro Trp Asp Phe Phe
Asp Tyr1 5 10219340DNAArtificial
SequenceSynthetic 219gacatcgtga tgacccagtc tccagactcc ctggctgtgt
ctctgggcga gagggccacc 60atcaactgca agtccagcca gagtgtttta tacagctcca
acaataagaa ctacttagct 120tggtaccagc agaaaccagg acagcctcct aagctgctca
tttactgggc atctacccgg 180gaatccgggg tccctgaccg attcagtggc agcgggtctg
ggacagattt cactctcacc 240atcagcagcc tgcaggctga agatgtggca gtttattact
gtcagcaata ttatagtact 300ccgtacactt ttggccaggg gaccaagctg gagatcaaac
340220113PRTArtificial SequenceSynthetic 220Asp
Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly1
5 10 15Glu Arg Ala Thr Ile Asn Cys Lys
Ser Ser Gln Ser Val Leu Tyr Ser20 25
30Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln35
40 45Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser
Thr Arg Glu Ser Gly Val50 55 60Pro Asp
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr65
70 75 80Ile Ser Ser Leu Gln Ala Glu
Asp Val Ala Val Tyr Tyr Cys Gln Gln85 90
95Tyr Tyr Ser Thr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile100
105 110Lys22136DNAArtificial
SequenceSynthetic 221cagagtgttt tatacagctc caacaataag aactac
3622212PRTArtificial SequenceSynthetic 222Gln Ser Val
Leu Tyr Ser Ser Asn Asn Lys Asn Tyr1 5
102239DNAArtificial SequenceSynthetic 223tgggcatct
92243PRTArtificial
SequenceSynthetic 224Trp Ala Ser122527DNAArtificial SequenceSynthetic
225cagcaatatt atagtactcc gtacact
272269PRTArtificial SequenceSynthetic 226Gln Gln Tyr Tyr Ser Thr Pro Tyr
Thr1 5227361DNAArtificial SequenceSynthetic 227caggtgcagt
tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg
tctctggtgg ctccatcggc agtggtggtt actactggag ctggatccgc 120cagcacccag
ggaagggcct ggagtggatt gggtacgtcc attacagtgg gaacacccac 180tacaacccgt
ccctcaagag tcgactttcc atatcaatag acacgtctaa gatccagttc 240tccctgaagc
tgagctctgt gactgccgcg gacacggccg tgtattactg tgcgagagcc 300ccccgtggat
accattactt tgcctactgg ggccagggaa ccctggtcac cgtctcctca 360g
361228120PRTArtificial SequenceSynthetic 228Gln Val Gln Leu Gln Glu Ser
Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10
15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Gly
Ser Gly20 25 30Gly Tyr Tyr Trp Ser Trp
Ile Arg Gln His Pro Gly Lys Gly Leu Glu35 40
45Trp Ile Gly Tyr Val His Tyr Ser Gly Asn Thr His Tyr Asn Pro Ser50
55 60Leu Lys Ser Arg Leu Ser Ile Ser Ile
Asp Thr Ser Lys Ile Gln Phe65 70 75
80Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val
Tyr Tyr85 90 95Cys Ala Arg Ala Pro Arg
Gly Tyr His Tyr Phe Ala Tyr Trp Gly Gln100 105
110Gly Thr Leu Val Thr Val Ser Ser115
12022930DNAArtificial SequenceSynthetic 229ggtggctcca tcggcagtgg
tggttactac 3023010PRTArtificial
SequenceSynthetic 230Gly Gly Ser Ile Gly Ser Gly Gly Tyr Tyr1
5 1023121DNAArtificial SequenceSynthetic 231gtccattaca
gtgggaacac c
212327PRTArtificial SequenceSynthetic 232Val His Tyr Ser Gly Asn Thr1
523336DNAArtificial SequenceSynthetic 233gcgagagccc cccgtggata
ccattacttt gcctac 3623412PRTArtificial
SequenceSynthetic 234Ala Arg Ala Pro Arg Gly Tyr His Tyr Phe Ala Tyr1
5 10235325DNAArtificial SequenceSynthetic
235gaaattgtgt tgacacaatc tccaggcacc ctgtctttgt ctccagggga aagagccacc
60ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa
120cctggccagg ctcccaggct cctcatcttt ggtgcatcca gcagggccac tggcatccca
180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag
240cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcaccgct cactttcggc
300ggagggacca aggtggagat caaac
325236108PRTArtificial SequenceSynthetic 236Glu Ile Val Leu Thr Gln Ser
Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10
15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser
Ser Ser20 25 30Tyr Leu Ala Trp Tyr Gln
Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu35 40
45Ile Phe Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser50
55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr
Leu Thr Ile Ser Arg Leu Glu65 70 75
80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser
Ser Pro85 90 95Leu Thr Phe Gly Gly Gly
Thr Lys Val Glu Ile Lys100 10523721DNAArtificial
SequenceSynthetic 237cagagtgtta gcagcagcta c
212387PRTArtificial SequenceSynthetic 238Gln Ser Val Ser
Ser Ser Tyr1 52399DNAArtificial SequenceSynthetic
239ggtgcatcc
92403PRTArtificial SequenceSynthetic 240Gly Ala Ser124127DNAArtificial
SequenceSynthetic 241cagcagtatg gtagctcacc gctcact
272429PRTArtificial SequenceSynthetic 242Gln Gln Tyr Gly
Ser Ser Pro Leu Thr1 5243361DNAArtificial SequenceSynthetic
243caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc
60acctgcactg tctctggtgg ctccatcagc agtggtggtt actactggag ctggatccgc
120cagtacccag ggaagggcct ggagtggatt ggttacgtcc attacagtgg gagcacccac
180tacaacccgt ccctcaagag tcgacttacc atatcaatag acacgtctaa gagccagttc
240tccctgaagc tgagctctgt gactgccgcg gacacggccg tgtattactg tgcgagagcc
300ccccgtggat accattactt tgcctactgg ggccagggaa ccctggtcac cgtctcctca
360g
361244120PRTArtificial SequenceSynthetic 244Gln Val Gln Leu Gln Glu Ser
Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10
15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser
Ser Gly20 25 30Gly Tyr Tyr Trp Ser Trp
Ile Arg Gln Tyr Pro Gly Lys Gly Leu Glu35 40
45Trp Ile Gly Tyr Val His Tyr Ser Gly Ser Thr His Tyr Asn Pro Ser50
55 60Leu Lys Ser Arg Leu Thr Ile Ser Ile
Asp Thr Ser Lys Ser Gln Phe65 70 75
80Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val
Tyr Tyr85 90 95Cys Ala Arg Ala Pro Arg
Gly Tyr His Tyr Phe Ala Tyr Trp Gly Gln100 105
110Gly Thr Leu Val Thr Val Ser Ser115
12024530DNAArtificial SequenceSynthetic 245ggtggctcca tcagcagtgg
tggttactac 3024610PRTArtificial
SequenceSynthetic 246Gly Gly Ser Ile Ser Ser Gly Gly Tyr Tyr1
5 1024721DNAArtificial SequenceSynthetic 247gtccattaca
gtgggagcac c
212487PRTArtificial SequenceSynthetic 248Val His Tyr Ser Gly Ser Thr1
524936DNAArtificial SequenceSynthetic 249gcgagagccc cccgtggata
ccattacttt gcctac 3625012PRTArtificial
SequenceSynthetic 250Ala Arg Ala Pro Arg Gly Tyr His Tyr Phe Ala Tyr1
5 10251325DNAArtificial SequenceSynthetic
251gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc
60ctctcctgca gggccagtca gagtgttagc agcaggtact tagcctggta ccagcagaaa
120cctggccagg ctcccaggct cctcatcttt ggtgcatcca gcagggccac tggcatacca
180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag
240cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcaccgct cactttcggc
300ggagggacca aggtggagat caaac
325252108PRTArtificial SequenceSynthetic 252Glu Ile Val Leu Thr Gln Ser
Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10
15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser
Ser Arg20 25 30Tyr Leu Ala Trp Tyr Gln
Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu35 40
45Ile Phe Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser50
55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr
Leu Thr Ile Ser Arg Leu Glu65 70 75
80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser
Ser Pro85 90 95Leu Thr Phe Gly Gly Gly
Thr Lys Val Glu Ile Lys100 10525321DNAArtificial
SequenceSynthetic 253cagagtgtta gcagcaggta c
212547PRTArtificial SequenceSynthetic 254Gln Ser Val Ser
Ser Arg Tyr1 52559DNAArtificial SequenceSynthetic
255ggtgcatcc
92563PRTArtificial SequenceSynthetic 256Gly Ala Ser125727DNAArtificial
SequenceSynthetic 257cagcagtatg gtagctcacc gctcact
272589PRTArtificial SequenceSynthetic 258Gln Gln Tyr Gly
Ser Ser Pro Leu Thr1 5259355DNAArtificial SequenceSynthetic
259caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc
60acctgcactg tctctggtgg ctccatcagc agtggtggtt actactggag ctggatccgc
120cagcacccag ggaagggcct ggagtggatt gggtacatct attacagtgg gagcacctac
180tacaacccgt ccctcaagag tcgaattatc atatcagtag acacgtctaa gaaccagttc
240tccctgaagc tgagctctgt gactgccgcg gacacggccg tgtattactg tgcgagagaa
300ggggctatgg tttttgacta ctggggccag ggaaccctgg tcaccgtctc ctcag
355260118PRTArtificial SequenceSynthetic 260Gln Val Gln Leu Gln Glu Ser
Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10
15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser
Ser Gly20 25 30Gly Tyr Tyr Trp Ser Trp
Ile Arg Gln His Pro Gly Lys Gly Leu Glu35 40
45Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser50
55 60Leu Lys Ser Arg Ile Ile Ile Ser Val
Asp Thr Ser Lys Asn Gln Phe65 70 75
80Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val
Tyr Tyr85 90 95Cys Ala Arg Glu Gly Ala
Met Val Phe Asp Tyr Trp Gly Gln Gly Thr100 105
110Leu Val Thr Val Ser Ser11526130DNAArtificial SequenceSynthetic
261ggtggctcca tcagcagtgg tggttactac
3026210PRTArtificial SequenceSynthetic 262Gly Gly Ser Ile Ser Ser Gly Gly
Tyr Tyr1 5 1026321DNAArtificial
SequenceSynthetic 263atctattaca gtgggagcac c
212647PRTArtificial SequenceSynthetic 264Ile Tyr Tyr Ser
Gly Ser Thr1 526530DNAArtificial SequenceSynthetic
265gcgagagaag gggctatggt ttttgactac
3026610PRTArtificial SequenceSynthetic 266Ala Arg Glu Gly Ala Met Val Phe
Asp Tyr1 5 10267322DNAArtificial
SequenceSynthetic 267gacatccagt tgacccagtc tccatccttc ctgtctgcat
ctgtaggaga cagagtcacc 60atcacttgct gggccagtca gggcattagc agttatttag
cctggtatca gcaaaaacca 120gggaaagccc ctaaactcct gatttatgct gcatccgctt
tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagaa ttcactctca
ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgtcaacag cttaatagtt
acccgttcac ttttggccag 300gggaccaagc tggagatcaa ac
322268107PRTArtificial SequenceSynthetic 268Asp
Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly1
5 10 15Asp Arg Val Thr Ile Thr Cys Trp
Ala Ser Gln Gly Ile Ser Ser Tyr20 25
30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile35
40 45Tyr Ala Ala Ser Ala Leu Gln Ser Gly Val
Pro Ser Arg Phe Ser Gly50 55 60Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65
70 75 80Glu Asp Phe Ala Thr Tyr Tyr
Cys Gln Gln Leu Asn Ser Tyr Pro Phe85 90
95Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys100
10526918DNAArtificial SequenceSynthetic 269cagggcatta gcagttat
182706PRTArtificial
SequenceSynthetic 270Gln Gly Ile Ser Ser Tyr1
52719DNAArtificial SequenceSynthetic 271gctgcatcc
92723PRTArtificial SequenceSynthetic
272Ala Ala Ser127327DNAArtificial SequenceSynthetic 273caacagctta
atagttaccc gttcact
272749PRTArtificial SequenceSynthetic 274Gln Gln Leu Asn Ser Tyr Pro Phe
Thr1 5275355DNAArtificial SequenceSynthetic 275caggtgcagc
tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg
tctctggtgg ctccatcagc agtggtggtt actactggag ctggatccgc 120cagcacccag
ggaagggcct ggagtggatt gggtacatct attacagtgg gagcacctac 180tacaacccgt
ccctcaagag tcgaattatc atatcagtag acacgtctaa gaaccagttc 240tccctgaagc
tgagctctgt gactgccgcg gacacggccg tgtattactg tgcgagagaa 300ggggctatgg
tttttgacta ctggggccag ggaaccctgg tcaccgtctc ctcag
355276118PRTArtificial SequenceSynthetic 276Gln Val Gln Leu Gln Glu Ser
Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10
15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser
Ser Gly20 25 30Gly Tyr Tyr Trp Ser Trp
Ile Arg Gln His Pro Gly Lys Gly Leu Glu35 40
45Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser50
55 60Leu Lys Ser Arg Ile Ile Ile Ser Val
Asp Thr Ser Lys Asn Gln Phe65 70 75
80Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val
Tyr Tyr85 90 95Cys Ala Arg Glu Gly Ala
Met Val Phe Asp Tyr Trp Gly Gln Gly Thr100 105
110Leu Val Thr Val Ser Ser11527730DNAArtificial SequenceSynthetic
277ggtggctcca tcagcagtgg tggttactac
3027810PRTArtificial SequenceSynthetic 278Gly Gly Ser Ile Ser Ser Gly Gly
Tyr Tyr1 5 1027921DNAArtificial
SequenceSynthetic 279atctattaca gtgggagcac c
212807PRTArtificial SequenceSynthetic 280Ile Tyr Tyr Ser
Gly Ser Thr1 528130DNAArtificial SequenceSynthetic
281gcgagagaag gggctatggt ttttgactac
3028210PRTArtificial SequenceSynthetic 282Ala Arg Glu Gly Ala Met Val Phe
Asp Tyr1 5 10283322DNAArtificial
SequenceSynthetic 283gacatccagt tgacccagtc tccatccttc ctgtctgcat
ctgtaggaga cagagtcacc 60atcacttgct gggccagtca gggcattagc agttatttag
cctggtatca gcaaaaacca 120gggaaagccc ctaaactcct gatttatgct gcatccgctt
tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagaa ttcactctca
ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgtcaacag cttaatagtt
acccgttcac ttttggccag 300gggaccaagc tggagatcaa ac
322284107PRTArtificial SequenceSynthetic 284Asp
Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly1
5 10 15Asp Arg Val Thr Ile Thr Cys Trp
Ala Ser Gln Gly Ile Ser Ser Tyr20 25
30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile35
40 45Tyr Ala Ala Ser Ala Leu Gln Ser Gly Val
Pro Ser Arg Phe Ser Gly50 55 60Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65
70 75 80Glu Asp Phe Ala Thr Tyr Tyr
Cys Gln Gln Leu Asn Ser Tyr Pro Phe85 90
95Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys100
10528518DNAArtificial SequenceSynthetic 285cagggcatta gcagttat
182866PRTArtificial
SequenceSynthetic 286Gln Gly Ile Ser Ser Tyr1
52879DNAArtificial SequenceSynthetic 287gctgcatcc
92883PRTArtificial SequenceSynthetic
288Ala Ala Ser128927DNAArtificial SequenceSynthetic 289caacagctta
atagttaccc gttcact
272909PRTArtificial SequenceSynthetic 290Gln Gln Leu Asn Ser Tyr Pro Phe
Thr1 5291355DNAArtificial SequenceSynthetic 291caggtgcagc
tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg
tctctggtgg ctccatcagc agtggtggtt actactggac ctggatccgc 120cagcacccag
ggaagggcct ggagtggatt gggtacatct attacagtgg gagcacctac 180tacaacccgt
ccctcaagag tcgagttatc atatcagtag acacgtctaa gaaccagttc 240tccctgaagc
tgagctctgt gactgccgcg gacacggccg tgtattactg tgcgagagaa 300ggggctatgg
tttttgacta ctggggccag ggaaccctgg tcaccgtctc ctcag
355292118PRTArtificial SequenceSynthetic 292Gln Val Gln Leu Gln Glu Ser
Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10
15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser
Ser Gly20 25 30Gly Tyr Tyr Trp Thr Trp
Ile Arg Gln His Pro Gly Lys Gly Leu Glu35 40
45Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser50
55 60Leu Lys Ser Arg Val Ile Ile Ser Val
Asp Thr Ser Lys Asn Gln Phe65 70 75
80Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val
Tyr Tyr85 90 95Cys Ala Arg Glu Gly Ala
Met Val Phe Asp Tyr Trp Gly Gln Gly Thr100 105
110Leu Val Thr Val Ser Ser11529330DNAArtificial SequenceSynthetic
293ggtggctcca tcagcagtgg tggttactac
3029410PRTArtificial SequenceSynthetic 294Gly Gly Ser Ile Ser Ser Gly Gly
Tyr Tyr1 5 1029521DNAArtificial
SequenceSynthetic 295atctattaca gtgggagcac c
212967PRTArtificial SequenceSynthetic 296Ile Tyr Tyr Ser
Gly Ser Thr1 529730DNAArtificial SequenceSynthetic
297gcgagagaag gggctatggt ttttgactac
3029810PRTArtificial SequenceSynthetic 298Ala Arg Glu Gly Ala Met Val Phe
Asp Tyr1 5 10299322DNAArtificial
SequenceSynthetic 299gacatccagt tgacccagtc tccatccttc ctgtctgcat
ctgtaggaga cagagtcacc 60atcacttgct gggccagtca gggcattagc agttatttag
cctggtatca gcaaaaacca 120gggaaagccc ctaagctcct gatctatgct gcatccgctt
tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagaa ttcactctca
caatcagcag cctgcagcct 240gaagattttg caacttatta ctgtcaacag cttaatagtt
acccgttcac ttttggccag 300gggaccaagc tggagatcaa ac
322300107PRTArtificial SequenceSynthetic 300Asp
Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly1
5 10 15Asp Arg Val Thr Ile Thr Cys Trp
Ala Ser Gln Gly Ile Ser Ser Tyr20 25
30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile35
40 45Tyr Ala Ala Ser Ala Leu Gln Ser Gly Val
Pro Ser Arg Phe Ser Gly50 55 60Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65
70 75 80Glu Asp Phe Ala Thr Tyr Tyr
Cys Gln Gln Leu Asn Ser Tyr Pro Phe85 90
95Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys100
10530118DNAArtificial SequenceSynthetic 301cagggcatta gcagttat
183026PRTArtificial
SequenceSynthetic 302Gln Gly Ile Ser Ser Tyr1
53039DNAArtificial SequenceSynthetic 303gctgcatcc
93043PRTArtificial SequenceSynthetic
304Ala Ala Ser130527DNAArtificial SequenceSynthetic 305caacagctta
atagttaccc gttcact
273069PRTArtificial SequenceSynthetic 306Gln Gln Leu Asn Ser Tyr Pro Phe
Thr1 5307355DNAArtificial SequenceSynthetic 307caggtgcagc
tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg
tctctggtgg ctccatcagc agtggtggtt actactggac ctggatccgc 120cagtacccag
ggaagggcct ggagtggatt gggtacatct attacagtgg gagcacctac 180tacaacccgt
ccctcaagag tcgagttatc atatcagtag acacgtctaa gaaccagttc 240tccctgaggc
tgagctctgt gactgccgcg gacacggccg tgtattactg tgcgagagaa 300ggggctatgg
tttttgacta ctggggccag ggaaccctgg tcaccgtctc ctcag
355308118PRTArtificial SequenceSynthetic 308Gln Val Gln Leu Gln Glu Ser
Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10
15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser
Ser Gly20 25 30Gly Tyr Tyr Trp Thr Trp
Ile Arg Gln Tyr Pro Gly Lys Gly Leu Glu35 40
45Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser50
55 60Leu Lys Ser Arg Val Ile Ile Ser Val
Asp Thr Ser Lys Asn Gln Phe65 70 75
80Ser Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val
Tyr Tyr85 90 95Cys Ala Arg Glu Gly Ala
Met Val Phe Asp Tyr Trp Gly Gln Gly Thr100 105
110Leu Val Thr Val Ser Ser11530930DNAArtificial SequenceSynthetic
309ggtggctcca tcagcagtgg tggttactac
3031010PRTArtificial SequenceSynthetic 310Gly Gly Ser Ile Ser Ser Gly Gly
Tyr Tyr1 5 1031121DNAArtificial
SequenceSynthetic 311atctattaca gtgggagcac c
213127PRTArtificial SequenceSynthetic 312Ile Tyr Tyr Ser
Gly Ser Thr1 531330DNAArtificial SequenceSynthetic
313gcgagagaag gggctatggt ttttgactac
3031410PRTArtificial SequenceSynthetic 314Ala Arg Glu Gly Ala Met Val Phe
Asp Tyr1 5 10315322DNAArtificial
SequenceSynthetic 315gacatccagt tgacccagtc tccatccttc ctgtctgcat
ctgtaggaga cagagtcacc 60atcacttgct gggccagtca gggcattagc agttatttag
cctggtatca gcaaaaacca 120gggaaagccc ctaagctcct gatctatgct gcatccgctt
tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagaa ttcactctca
caatcagcag cctgcagcct 240gaagattttg caacttatta ctgtcaacag cttaatagtt
acccgttcac ttttggccag 300gggaccaagc tggagatcaa ac
322316107PRTArtificial SequenceSynthetic 316Asp
Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly1
5 10 15Asp Arg Val Thr Ile Thr Cys Trp
Ala Ser Gln Gly Ile Ser Ser Tyr20 25
30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile35
40 45Tyr Ala Ala Ser Ala Leu Gln Ser Gly Val
Pro Ser Arg Phe Ser Gly50 55 60Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65
70 75 80Glu Asp Phe Ala Thr Tyr Tyr
Cys Gln Gln Leu Asn Ser Tyr Pro Phe85 90
95Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys100
10531718DNAArtificial SequenceSynthetic 317cagggcatta gcagttat
183186PRTArtificial
SequenceSynthetic 318Gln Gly Ile Ser Ser Tyr1
53199DNAArtificial SequenceSynthetic 319gctgcatcc
93203PRTArtificial SequenceSynthetic
320Ala Ala Ser132127DNAArtificial SequenceSynthetic 321caacagctta
atagttaccc gttcact
273229PRTArtificial SequenceSynthetic 322Gln Gln Leu Asn Ser Tyr Pro Phe
Thr1 5323358DNAArtificial SequenceSynthetic 323caggttcacc
tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaggg
cttctggtta cacctttacc aactatggta tcacctgggt gcgacaggcc 120cctggacaag
ggcttgagtg gatgggatgg atcagcgcta acagtggtaa cacagactct 180gcacagaagt
tccaggccag agtcaccatg accacagaca catccacgac cacagcctac 240atggaactga
ggagcctgag atctgacgac acggccgtgt attattgtgc gacgtatagt 300tggaactttc
actggttcga cccctggggc cagggaaccc tggtcaccgt ctcctcag
358324119PRTArtificial SequenceSynthetic 324Gln Val His Leu Val Gln Ser
Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10
15Ser Val Lys Val Ser Cys Arg Ala Ser Gly Tyr Thr Phe Thr
Asn Tyr20 25 30Gly Ile Thr Trp Val Arg
Gln Ala Pro Gly Gln Gly Leu Glu Trp Met35 40
45Gly Trp Ile Ser Ala Asn Ser Gly Asn Thr Asp Ser Ala Gln Lys Phe50
55 60Gln Ala Arg Val Thr Met Thr Thr Asp
Thr Ser Thr Thr Thr Ala Tyr65 70 75
80Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr
Tyr Cys85 90 95Ala Thr Tyr Ser Trp Asn
Phe His Trp Phe Asp Pro Trp Gly Gln Gly100 105
110Thr Leu Val Thr Val Ser Ser11532524DNAArtificial
SequenceSynthetic 325ggttacacct ttaccaacta tggt
243268PRTArtificial SequenceSynthetic 326Gly Tyr Thr Phe
Thr Asn Tyr Gly1 532724DNAArtificial SequenceSynthetic
327atcagcgcta acagtggtaa caca
243288PRTArtificial SequenceSynthetic 328Ile Ser Ala Asn Ser Gly Asn Thr1
532936DNAArtificial SequenceSynthetic 329gcgacgtata
gttggaactt tcactggttc gacccc
3633012PRTArtificial SequenceSynthetic 330Ala Thr Tyr Ser Trp Asn Phe His
Trp Phe Asp Pro1 5 10331325DNAArtificial
SequenceSynthetic 331gaaattgtgt tgacgcagtc tccaggcact ctgtctttgt
ctccagggga aagagtcacc 60ctctcctgca gggccagtca gagtgtcagt accaactact
taacctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctat ggtgcatcca
gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcattc
tcaccatcag aagtctggag 240cctgaagatt ttgcagtgta ttactgtcag cagtgtggtg
gctcaccgtg gacgttcggc 300caagggacca gggtggaaat caaac
325332108PRTArtificial SequenceSynthetic 332Glu
Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1
5 10 15Glu Arg Val Thr Leu Ser Cys Arg
Ala Ser Gln Ser Val Ser Thr Asn20 25
30Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu35
40 45Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly
Ile Pro Asp Arg Phe Ser50 55 60Gly Ser
Gly Ser Gly Thr Asp Phe Ile Leu Thr Ile Arg Ser Leu Glu65
70 75 80Pro Glu Asp Phe Ala Val Tyr
Tyr Cys Gln Gln Cys Gly Gly Ser Pro85 90
95Trp Thr Phe Gly Gln Gly Thr Arg Val Glu Ile Lys100
10533321DNAArtificial SequenceSynthetic 333cagagtgtca gtaccaacta c
213347PRTArtificial
SequenceSynthetic 334Gln Ser Val Ser Thr Asn Tyr1
53359DNAArtificial SequenceSynthetic 335ggtgcatcc
93363PRTArtificial SequenceSynthetic
336Gly Ala Ser133727DNAArtificial SequenceSynthetic 337cagcagtgtg
gtggctcacc gtggacg
273389PRTArtificial SequenceSynthetic 338Gln Gln Cys Gly Gly Ser Pro Trp
Thr1 5339355DNAArtificial SequenceSynthetic 339caggtgcagc
tggtggagtc tgggggaggc gtggtccagc ctgggaggtc tctgagactc 60tcctgtgcag
cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg
gactggagtg ggtggcagtt atatggtatg atggaagtaa taaatattat 180ggagactccg
tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga
acagcctgag agccgaggac acggctgtat attactgtgc gagagatgga 300gtagacggtg
cttttgatat ttggggccaa gggacaacgg tcaccgtctc ttcag
355340118PRTArtificial SequenceSynthetic 340Gln Val Gln Leu Val Glu Ser
Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10
15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
Ser Tyr20 25 30Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val35 40
45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Gly Asp Ser Val50
55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys85 90 95Ala Arg Asp Gly Val Asp
Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr100 105
110Thr Val Thr Val Ser Ser11534124DNAArtificial SequenceSynthetic
341ggattcacct tcagtagcta tggc
243428PRTArtificial SequenceSynthetic 342Gly Phe Thr Phe Ser Ser Tyr Gly1
534324DNAArtificial SequenceSynthetic 343atatggtatg
atggaagtaa taaa
243448PRTArtificial SequenceSynthetic 344Ile Trp Tyr Asp Gly Ser Asn Lys1
534533DNAArtificial SequenceSynthetic 345gcgagagatg
gagtagacgg tgcttttgat att
3334611PRTArtificial SequenceSynthetic 346Ala Arg Asp Gly Val Asp Gly Ala
Phe Asp Ile1 5 10347322DNAArtificial
SequenceSynthetic 347gccatccaga tgacccagtc tccatcctcc ctgtctgcat
ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca ggacattaga aatgatttag
gctggtatca gcagaaacca 120gggaaagccc ctaaactcct gatctatgct gcatccagtt
tacaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tggcacagat ttcactctca
ccatcagcag actgcagcct 240gaagattttg caacttatta ctgtcaacaa gattacaatt
acctgtatac ttttggccag 300gggaccaacc tggagatcaa ac
322348107PRTArtificial SequenceSynthetic 348Ala
Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1
5 10 15Asp Arg Val Thr Ile Thr Cys Arg
Ala Ser Gln Asp Ile Arg Asn Asp20 25
30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile35
40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val
Pro Ser Arg Phe Ser Gly50 55 60Ser Gly
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Gln Pro65
70 75 80Glu Asp Phe Ala Thr Tyr Tyr
Cys Gln Gln Asp Tyr Asn Tyr Leu Tyr85 90
95Thr Phe Gly Gln Gly Thr Asn Leu Glu Ile Lys100
10534918DNAArtificial SequenceSynthetic 349caggacatta gaaatgat
183506PRTArtificial
SequenceSynthetic 350Gln Asp Ile Arg Asn Asp1
53519DNAArtificial SequenceSynthetic 351gctgcatcc
93523PRTArtificial SequenceSynthetic
352Ala Ala Ser135327DNAArtificial SequenceSynthetic 353caacaagatt
acaattacct gtatact
273549PRTArtificial SequenceSynthetic 354Gln Gln Asp Tyr Asn Tyr Leu Tyr
Thr1 5355364DNAArtificial SequenceSynthetic 355gaggtgcagt
tggtggagtc ggggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgaag
cctctggatt cacctttgat aactattata tgacctgggt ccgccagact 120ccagggaagg
ggctggagtg ggtggccaac ataaaggaag atggaaatga tagatactat 180gtggactctg
tgaagggccg cttcaccatc tccagagaca acgccaagca gtcactgttt 240ctacaaatga
acagtctgag agccgaggac acggctgttt attactgtgc gagagaattt 300tggagtggcc
ctcactacgg tttggacgtc tggggccaag ggaccacggt caccgtctcc 360tcag
364356121PRTArtificial SequenceSynthetic 356Glu Val Gln Leu Val Glu Ser
Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10
15Ser Leu Arg Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Asp
Asn Tyr20 25 30Tyr Met Thr Trp Val Arg
Gln Thr Pro Gly Lys Gly Leu Glu Trp Val35 40
45Ala Asn Ile Lys Glu Asp Gly Asn Asp Arg Tyr Tyr Val Asp Ser Val50
55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ala Lys Gln Ser Leu Phe65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys85 90 95Ala Arg Glu Phe Trp Ser
Gly Pro His Tyr Gly Leu Asp Val Trp Gly100 105
110Gln Gly Thr Thr Val Thr Val Ser Ser115
12035724DNAArtificial SequenceSynthetic 357ggattcacct ttgataacta ttat
243588PRTArtificial
SequenceSynthetic 358Gly Phe Thr Phe Asp Asn Tyr Tyr1
535924DNAArtificial SequenceSynthetic 359ataaaggaag atggaaatga taga
243608PRTArtificial
SequenceSynthetic 360Ile Lys Glu Asp Gly Asn Asp Arg1
536142DNAArtificial SequenceSynthetic 361gcgagagaat tttggagtgg ccctcactac
ggtttggacg tc 4236214PRTArtificial
SequenceSynthetic 362Ala Arg Glu Phe Trp Ser Gly Pro His Tyr Gly Leu Asp
Val1 5 10363322DNAArtificial
SequenceSynthetic 363gccctccaga tgacccagtc tccatcctcc ctgtctgcac
ctgtaggcga cagagtcacc 60atcacttgcc gggcaagtca ggacgttaga aataatttag
gctggtatca gcagaaacca 120gggaatgccc ctaaattcct gatctatgct gcatccagtt
tacaaagtgg aatcccatca 180aggttcagcg gcagtggatc tggctcagat ttcactctca
ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgtctacaa gattacaatt
accctccgac gttcggccag 300gggaccaagg tggaaatcaa gc
322364107PRTArtificial SequenceSynthetic 364Ala
Leu Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Pro Val Gly1
5 10 15Asp Arg Val Thr Ile Thr Cys Arg
Ala Ser Gln Asp Val Arg Asn Asn20 25
30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Asn Ala Pro Lys Phe Leu Ile35
40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Ile
Pro Ser Arg Phe Ser Gly50 55 60Ser Gly
Ser Gly Ser Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65
70 75 80Glu Asp Phe Ala Thr Tyr Tyr
Cys Leu Gln Asp Tyr Asn Tyr Pro Pro85 90
95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys100
10536518DNAArtificial SequenceSynthetic 365caggacgtta gaaataat
183666PRTArtificial
SequenceSynthetic 366Gln Asp Val Arg Asn Asn1
53679DNAArtificial SequenceSynthetic 367gctgcatcc
93683PRTArtificial SequenceSynthetic
368Ala Ala Ser136927DNAArtificial SequenceSynthetic 369ctacaagatt
acaattaccc tccgacg
273709PRTArtificial SequenceSynthetic 370Leu Gln Asp Tyr Asn Tyr Pro Pro
Thr1 5371370DNAArtificial SequenceSynthetic 371caggtgcagc
tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag
cgtctggatt caccttcagt agttatggca tgcactgggt ccgccaggct 120ccaggcaagg
ggctggagtg ggtggcagtt ttatggtatg atggaagtaa taaaaactat 180gtagactccg
tgaagggccg attcaccatc tcaagagaca attccaagaa cacgctgtat 240ctgcaaatga
acagcctgag agccgaggac acggctgtgt attactgtgc gagagatcac 300gattttagga
gtggttatga ggggtggttc gacccctggg gccagggaac cttggtcacc 360gtctcctcag
370372123PRTArtificial SequenceSynthetic 372Gln Val Gln Leu Val Glu Ser
Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10
15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
Ser Tyr20 25 30Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val35 40
45Ala Val Leu Trp Tyr Asp Gly Ser Asn Lys Asn Tyr Val Asp Ser Val50
55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys85 90 95Ala Arg Asp His Asp Phe
Arg Ser Gly Tyr Glu Gly Trp Phe Asp Pro100 105
110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser115
12037324DNAArtificial SequenceSynthetic 373ggattcacct tcagtagtta tggc
243748PRTArtificial
SequenceSynthetic 374Gly Phe Thr Phe Ser Ser Tyr Gly1
537524DNAArtificial SequenceSynthetic 375ttatggtatg atggaagtaa taaa
243768PRTArtificial
SequenceSynthetic 376Leu Trp Tyr Asp Gly Ser Asn Lys1
537748DNAArtificial SequenceSynthetic 377gcgagagatc acgattttag gagtggttat
gaggggtggt tcgacccc 4837816PRTArtificial
SequenceSynthetic 378Ala Arg Asp His Asp Phe Arg Ser Gly Tyr Glu Gly Trp
Phe Asp Pro1 5 10
15379322DNAArtificial SequenceSynthetic 379gaaattgtgt tgacacagtc
tccagccacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca
gagtgttcgc agctacttag cctggtacca acagaaacct 120ggccaggctc ccaggctcct
catctatgat gcatccaaca gggccactgg catcccagcc 180aggttcagtg gcagtgggtc
tgggacagac ttcactctca ccatcagcag cctagagcct 240gaagattttg cagtttatta
ctgtcagcac cgtagcaact ggcctcccac tttcggcgga 300gggaccgagg tggaggtcag
ac 322380107PRTArtificial
SequenceSynthetic 380Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu
Ser Pro Gly1 5 10 15Glu
Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Arg Ser Tyr20
25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala
Pro Arg Leu Leu Ile35 40 45Tyr Asp Ala
Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly50 55
60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
Leu Glu Pro65 70 75
80Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Arg Ser Asn Trp Pro Pro85
90 95Thr Phe Gly Gly Gly Thr Glu Val Glu Val
Arg100 10538118DNAArtificial SequenceSynthetic
381cagagtgttc gcagctac
183826PRTArtificial SequenceSynthetic 382Gln Ser Val Arg Ser Tyr1
53839DNAArtificial SequenceSynthetic 383gatgcatcc
93843PRTArtificial
SequenceSynthetic 384Asp Ala Ser138527DNAArtificial SequenceSynthetic
385cagcaccgta gcaactggcc tcccact
273869PRTArtificial SequenceSynthetic 386Gln His Arg Ser Asn Trp Pro Pro
Thr1 538716DNAArtificial SequenceSynthetic 387taccggctcc
cgatgg
1638819DNAArtificial SequenceSynthetic 388ggcggctaag gtgtttgga
1938922DNAArtificial
SequenceSynthetic 389ttgggaatga ggaaagcaaa ct
2239018DNAArtificial SequenceSynthetic 390ctgaagtacc
ggaggaga
1839120DNAArtificial SequenceSynthetic 391atcacgctgg tggtcctctt
2039216DNAArtificial
SequenceSynthetic 392gctgcggcga gtgctt
1639323DNAArtificial SequenceSynthetic 393tggcaaatgc
tggacccaac aca
2339419DNAArtificial SequenceSynthetic 394gggtcctggc atcttgtcc
1939522DNAArtificial
SequenceSynthetic 395gcagatgaaa aactgggaac ca
22396372DNAArtificial SequenceSynthetic 396caggtgcagc
tggtgcagtc aggtccagga ctggtgaagc cctcgcagaa cctctcactc 60acctgtgcca
tctccggaga cagtgtctct agtgatagtg ctgcttggaa ctggatcagg 120cagtccccat
cgagaggcct tgagtggctg ggaaggacat actacaggtc caagtggtat 180aatgattatg
cagtatctgt gaaaagtcga ataaccttca acccagatac atccaagaac 240cacatctccc
tgcagctgaa ctctgtgact cccgaggaca cggctatcta ttactgtgca 300agagaggggg
ataattggaa ttacggctgg ctcgacccct ggggccaggg aaccacggtc 360accgtctcct
ca
372397124PRTArtificial SequenceSynthetic 397Gln Val Gln Leu Val Gln Ser
Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10
15Asn Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser
Ser Asp20 25 30Ser Ala Ala Trp Asn Trp
Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu35 40
45Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Asp Tyr Ala50
55 60Val Ser Val Lys Ser Arg Ile Thr Phe
Asn Pro Asp Thr Ser Lys Asn65 70 75
80His Ile Ser Leu Gln Leu Asn Ser Val Thr Pro Glu Asp Thr
Ala Ile85 90 95Tyr Tyr Cys Ala Arg Glu
Gly Asp Asn Trp Asn Tyr Gly Trp Leu Asp100 105
110Pro Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser115
12039830DNAArtificial SequenceSynthetic 398ggagacagtg tctctagtga
tagtgctgct 3039910PRTArtificial
SequenceSynthetic 399Gly Asp Ser Val Ser Ser Asp Ser Ala Ala1
5 1040027DNAArtificial SequenceSynthetic 400acatactaca
ggtccaagtg gtataat
274019PRTArtificial SequenceSynthetic 401Thr Tyr Tyr Arg Ser Lys Trp Tyr
Asn1 540242DNAArtificial SequenceSynthetic 402gcaagagagg
gggataattg gaattacggc tggctcgacc cc
4240314PRTArtificial SequenceSynthetic 403Ala Arg Glu Gly Asp Asn Trp Asn
Tyr Gly Trp Leu Asp Pro1 5
10404336DNAArtificial SequenceSynthetic 404gacatccagt tgacccagtc
tccactctcc ctgcccgtca cccctggaga gccggcctcc 60atctcctgca ggtctagtca
gagcctcctt cttagtaatg gatacaacta tttggattgg 120tacctgcaga agccagggca
gtctccacaa ctcctgatct atttggtttc tagtcgggcc 180tccggggtcc ctgacaggtt
cagtggcagt ggatccggca cagattttac actgaaaatc 240agcagagtgg aggctgagga
ttttggaatt tattattgta tgcaagctct acaaactccg 300tacacttttg gccgggggac
caaggtggaa atcaaa 336405112PRTArtificial
SequenceSynthetic 405Asp Ile Gln Leu Thr Gln Ser Pro Leu Ser Leu Pro Val
Thr Pro Gly1 5 10 15Glu
Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Leu Ser20
25 30Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln
Lys Pro Gly Gln Ser35 40 45Pro Gln Leu
Leu Ile Tyr Leu Val Ser Ser Arg Ala Ser Gly Val Pro50 55
60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
Leu Lys Ile65 70 75
80Ser Arg Val Glu Ala Glu Asp Phe Gly Ile Tyr Tyr Cys Met Gln Ala85
90 95Leu Gln Thr Pro Tyr Thr Phe Gly Arg Gly
Thr Lys Val Glu Ile Lys100 105
11040633DNAArtificial SequenceSynthetic 406cagagcctcc ttcttagtaa
tggatacaac tat 3340711PRTArtificial
SequenceSynthetic 407Gln Ser Leu Leu Leu Ser Asn Gly Tyr Asn Tyr1
5 104089DNAArtificial SequenceSynthetic
408ttggtttct
94093PRTArtificial SequenceSynthetic 409Leu Val Ser141027DNAArtificial
SequenceSynthetic 410atgcaagctc tacaaactcc gtacact
274119PRTArtificial SequenceSynthetic 411Met Gln Ala Leu
Gln Thr Pro Tyr Thr1 5412360DNAArtificial SequenceSynthetic
412caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc
60acctgcactg tctctggtgg ctccgtcagc agtggtaatt actactggag ctgggtccgc
120caacacccag ggaagggcct ggagtggttt ggttacatca aaaacagtgg gggcacctac
180tacaacccgt ccctcaagag tcgaattacc atatcagtag acacgtctaa gaaccacttc
240tccctgaggc tgagctctat gacggccgcg gacacggccg tgtattactg tgcgagagct
300ggttcgggga gtcactactt tgactactgg ggccagggaa ccctggtcac cgtctcctca
360413120PRTArtificial SequenceSynthetic 413Gln Val Gln Leu Gln Glu Ser
Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10
15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser
Ser Gly20 25 30Asn Tyr Tyr Trp Ser Trp
Val Arg Gln His Pro Gly Lys Gly Leu Glu35 40
45Trp Phe Gly Tyr Ile Lys Asn Ser Gly Gly Thr Tyr Tyr Asn Pro Ser50
55 60Leu Lys Ser Arg Ile Thr Ile Ser Val
Asp Thr Ser Lys Asn His Phe65 70 75
80Ser Leu Arg Leu Ser Ser Met Thr Ala Ala Asp Thr Ala Val
Tyr Tyr85 90 95Cys Ala Arg Ala Gly Ser
Gly Ser His Tyr Phe Asp Tyr Trp Gly Gln100 105
110Gly Thr Leu Val Thr Val Ser Ser115
12041430DNAArtificial SequenceSynthetic 414ggtggctccg tcagcagtgg
taattactac 3041510PRTArtificial
SequenceSynthetic 415Gly Gly Ser Val Ser Ser Gly Asn Tyr Tyr1
5 1041621DNAArtificial SequenceSynthetic 416atcaaaaaca
gtgggggcac c
214177PRTArtificial SequenceSynthetic 417Ile Lys Asn Ser Gly Gly Thr1
541836DNAArtificial SequenceSynthetic 418gcgagagctg gttcggggag
tcactacttt gactac 3641912PRTArtificial
SequenceSynthetic 419Ala Arg Ala Gly Ser Gly Ser His Tyr Phe Asp Tyr1
5 10420324DNAArtificial SequenceSynthetic
420gacatccagt tgacccagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc
60ctctcctgca gggccagtca gagtgttagc agcaactact tagcctggta ccagcagaaa
120cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca
180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag
240cctgaagatt gtgcagtgta ttactgtcag cagtacggtt actcaccgat caccttcggc
300caagggacca agctggagat caaa
324421108PRTArtificial SequenceSynthetic 421Asp Ile Gln Leu Thr Gln Ser
Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10
15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser
Ser Asn20 25 30Tyr Leu Ala Trp Tyr Gln
Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu35 40
45Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser50
55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr
Leu Thr Ile Ser Arg Leu Glu65 70 75
80Pro Glu Asp Cys Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Tyr
Ser Pro85 90 95Ile Thr Phe Gly Gln Gly
Thr Lys Leu Glu Ile Lys100 10542221DNAArtificial
SequenceSynthetic 422cagagtgtta gcagcaacta c
214237PRTArtificial SequenceSynthetic 423Gln Ser Val Ser
Ser Asn Tyr1 54249DNAArtificial SequenceSynthetic
424ggtgcatcc
94253PRTArtificial SequenceSynthetic 425Gly Ala Ser142627DNAArtificial
SequenceSynthetic 426cagcagtacg gttactcacc gatcacc
274279PRTArtificial SequenceSynthetic 427Gln Gln Tyr Gly
Tyr Ser Pro Ile Thr1 5428369DNAArtificial SequenceSynthetic
428gaggtgcagc tggtgcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc
60tcctgtgcag cgtctggatt caccttcagt agttatggca tgcactgggt ccgccaggct
120ccaggcaagg ggctggagtg ggtgtcattt ttatggtatg atggaactaa taaaaactat
180gtagagtccg tgaagggccg attcaccatc tcaagagaca attccaagaa tatgctgtat
240ctggaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatcac
300gattttagga gtggttatga ggggtggttc gacccctggg gccagggaac cctggtcacc
360gtctcctca
369429123PRTArtificial SequenceSynthetic 429Glu Val Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10
15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
Ser Tyr20 25 30Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val35 40
45Ser Phe Leu Trp Tyr Asp Gly Thr Asn Lys Asn Tyr Val Glu Ser Val50
55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Met Leu Tyr65 70 75
80Leu Glu Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys85 90 95Ala Arg Asp His Asp Phe
Arg Ser Gly Tyr Glu Gly Trp Phe Asp Pro100 105
110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser115
12043024DNAArtificial SequenceSynthetic 430ggattcacct tcagtagtta tggc
244318PRTArtificial
SequenceSynthetic 431Gly Phe Thr Phe Ser Ser Tyr Gly1
543224DNAArtificial SequenceSynthetic 432ttatggtatg atggaactaa taaa
244338PRTArtificial
SequenceSynthetic 433Leu Trp Tyr Asp Gly Thr Asn Lys1
543448DNAArtificial SequenceSynthetic 434gcgagagatc acgattttag gagtggttat
gaggggtggt tcgacccc 4843516PRTArtificial
SequenceSynthetic 435Ala Arg Asp His Asp Phe Arg Ser Gly Tyr Glu Gly Trp
Phe Asp Pro1 5 10
15436321DNAArtificial SequenceSynthetic 436gaaatagtga tgacacagtc
tccagccacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca
gagtgttagc agctacttag cctggtacca acagaaacct 120ggccaggctc ccaggctcct
catctatgat gcatccaaca gggccactgg catcccagcc 180aggttcagtg gcagtgggtc
tgggacagac ttcactctca ccatcagcag cctagagcct 240gaagattttg cagtttatta
ctgtcaacac cgtagcaact ggcctcccac tttcggcgga 300gggaccaagg tggaaatcaa a
321437107PRTArtificial
SequenceSynthetic 437Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu
Ser Pro Gly1 5 10 15Glu
Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr20
25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala
Pro Arg Leu Leu Ile35 40 45Tyr Asp Ala
Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly50 55
60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
Leu Glu Pro65 70 75
80Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Arg Ser Asn Trp Pro Pro85
90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
Lys100 10543818DNAArtificial SequenceSynthetic
438cagagtgtta gcagctac
184396PRTArtificial SequenceSynthetic 439Gln Ser Val Ser Ser Tyr1
54409DNAArtificial SequenceSynthetic 440gatgcatcc
94413PRTArtificial
SequenceSynthetic 441Asp Ala Ser144227DNAArtificial SequenceSynthetic
442caacaccgta gcaactggcc tcccact
274439PRTArtificial SequenceSynthetic 443Gln His Arg Ser Asn Trp Pro Pro
Thr1 5444366DNAArtificial SequenceSynthetic 444caggtacagc
tgcagcagtc gggtccagga ctgctgaaac cttcacagac cctgtccctc 60acctgctctg
tctctggtgg ctccatcagc agtggtaatt actactggac ctggatccgc 120cagcacccag
ggaagggcct ggagtggatt gggtacatca agaacagtgg aagcgcctac 180tacaatccgt
ccctcaagag tcgacttacc atgtcaatag acacgtctca gaaccacttc 240tccttgattt
tgacttctgt gactgccgcg gacacggcct tatattactg tgcgagagat 300gaaaatatag
cagttcgtca tgcttttgat atctggggcc aagggacatc ggtcaccgtc 360tcctca
366445122PRTArtificial SequenceSynthetic 445Gln Val Gln Leu Gln Gln Ser
Gly Pro Gly Leu Leu Lys Pro Ser Gln1 5 10
15Thr Leu Ser Leu Thr Cys Ser Val Ser Gly Gly Ser Ile Ser
Ser Gly20 25 30Asn Tyr Tyr Trp Thr Trp
Ile Arg Gln His Pro Gly Lys Gly Leu Glu35 40
45Trp Ile Gly Tyr Ile Lys Asn Ser Gly Ser Ala Tyr Tyr Asn Pro Ser50
55 60Leu Lys Ser Arg Leu Thr Met Ser Ile
Asp Thr Ser Gln Asn His Phe65 70 75
80Ser Leu Ile Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Leu
Tyr Tyr85 90 95Cys Ala Arg Asp Glu Asn
Ile Ala Val Arg His Ala Phe Asp Ile Trp100 105
110Gly Gln Gly Thr Ser Val Thr Val Ser Ser115
12044630DNAArtificial SequenceSynthetic 446ggtggctcca tcagcagtgg
taattactac 3044710PRTArtificial
SequenceSynthetic 447Gly Gly Ser Ile Ser Ser Gly Asn Tyr Tyr1
5 1044821DNAArtificial SequenceSynthetic 448atcaagaaca
gtggaagcgc c
214497PRTArtificial SequenceSynthetic 449Ile Lys Asn Ser Gly Ser Ala1
545042DNAArtificial SequenceSynthetic 450gcgagagatg aaaatatagc
agttcgtcat gcttttgata tc 4245114PRTArtificial
SequenceSynthetic 451Ala Arg Asp Glu Asn Ile Ala Val Arg His Ala Phe Asp
Ile1 5 10452324DNAArtificial
SequenceSynthetic 452gaaatagtgt tgacacagtc tccaggcgcc ctgtctttgt
ctccaggaga aagagccacc 60ctctcctgta gggccagtcg gactgttagc agcagctact
tagcctggta ccaacagaaa 120cctggccagg ctcccaggct cctcatctat ggtacatcca
gccgggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc
tcaccatcac cagactggag 240cctgaagatt ttgcaatata ttactgtcag cagtctggtt
actcacctct cactttcggc 300ggagggacca aggtggaaat caaa
324453108PRTArtificial SequenceSynthetic 453Glu
Ile Val Leu Thr Gln Ser Pro Gly Ala Leu Ser Leu Ser Pro Gly1
5 10 15Glu Arg Ala Thr Leu Ser Cys Arg
Ala Ser Arg Thr Val Ser Ser Ser20 25
30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu35
40 45Ile Tyr Gly Thr Ser Ser Arg Ala Thr Gly
Ile Pro Asp Arg Phe Ser50 55 60Gly Ser
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Arg Leu Glu65
70 75 80Pro Glu Asp Phe Ala Ile Tyr
Tyr Cys Gln Gln Ser Gly Tyr Ser Pro85 90
95Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys100
10545421DNAArtificial SequenceSynthetic 454cggactgtta gcagcagcta c
214557PRTArtificial
SequenceSynthetic 455Arg Thr Val Ser Ser Ser Tyr1
54569DNAArtificial SequenceSynthetic 456ggtacatcc
94573PRTArtificial SequenceSynthetic
457Gly Thr Ser145827DNAArtificial SequenceSynthetic 458cagcagtctg
gttactcacc tctcact
274599PRTArtificial SequenceSynthetic 459Gln Gln Ser Gly Tyr Ser Pro Leu
Thr1 5460357DNAArtificial SequenceSynthetic 460caggtgcagc
tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg
tctctgatga ctccatcaac aatgttgaat cctactggac ctggatccgc 120caacacccag
ggaagggcct ggagtggatt ggatacatca aatacactgg gggcatccac 180tataacccgt
ccctcaagag tcgactcgcc atatcagtgg acacgtcaaa gaaccagttc 240tccctgaaaa
tgaactctgt gactgccgcg gacacggcca aatattactg tgcgagagca 300cgtggaagtc
atacttttga tgtctggggc caggggacaa cggtcaccgt ctcctca
357461119PRTArtificial SequenceSynthetic 461Gln Val Gln Leu Gln Glu Ser
Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10
15Thr Leu Ser Leu Thr Cys Thr Val Ser Asp Asp Ser Ile Asn
Asn Val20 25 30Glu Ser Tyr Trp Thr Trp
Ile Arg Gln His Pro Gly Lys Gly Leu Glu35 40
45Trp Ile Gly Tyr Ile Lys Tyr Thr Gly Gly Ile His Tyr Asn Pro Ser50
55 60Leu Lys Ser Arg Leu Ala Ile Ser Val
Asp Thr Ser Lys Asn Gln Phe65 70 75
80Ser Leu Lys Met Asn Ser Val Thr Ala Ala Asp Thr Ala Lys
Tyr Tyr85 90 95Cys Ala Arg Ala Arg Gly
Ser His Thr Phe Asp Val Trp Gly Gln Gly100 105
110Thr Thr Val Thr Val Ser Ser11546230DNAArtificial
SequenceSynthetic 462gatgactcca tcaacaatgt tgaatcctac
3046310PRTArtificial SequenceSynthetic 463Asp Asp Ser
Ile Asn Asn Val Glu Ser Tyr1 5
1046421DNAArtificial SequenceSynthetic 464atcaaataca ctgggggcat c
214657PRTArtificial
SequenceSynthetic 465Ile Lys Tyr Thr Gly Gly Ile1
546633DNAArtificial SequenceSynthetic 466gcgagagcac gtggaagtca tacttttgat
gtc 3346711PRTArtificial
SequenceSynthetic 467Ala Arg Ala Arg Gly Ser His Thr Phe Asp Val1
5 10468324DNAArtificial SequenceSynthetic
468gccatccggt tgacccagtc tccaggcacc ctgtcttggt ctccagggga aagagccacc
60ctctcctgca gggccagtca gagtgttagc agtaactact tagcctggta ccagcagaaa
120cctggccagg ctccccgact cctcatttat ggtgcatcca gcagggtcgc tggcatccca
180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag
240cctgaagatt ttgcactgta ttattgtcag caatatagta ggtcaccgat caccttcggc
300caagggacca agctggagat caaa
324469108PRTArtificial SequenceSynthetic 469Ala Ile Arg Leu Thr Gln Ser
Pro Gly Thr Leu Ser Trp Ser Pro Gly1 5 10
15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser
Ser Asn20 25 30Tyr Leu Ala Trp Tyr Gln
Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu35 40
45Ile Tyr Gly Ala Ser Ser Arg Val Ala Gly Ile Pro Asp Arg Phe Ser50
55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr
Leu Thr Ile Ser Arg Leu Glu65 70 75
80Pro Glu Asp Phe Ala Leu Tyr Tyr Cys Gln Gln Tyr Ser Arg
Ser Pro85 90 95Ile Thr Phe Gly Gln Gly
Thr Lys Leu Glu Ile Lys100 10547021DNAArtificial
SequenceSynthetic 470cagagtgtta gcagtaacta c
214717PRTArtificial SequenceSynthetic 471Gln Ser Val Ser
Ser Asn Tyr1 54729DNAArtificial SequenceSynthetic
472ggtgcatcc
94733PRTArtificial SequenceSynthetic 473Gly Ala Ser147427DNAArtificial
SequenceSynthetic 474cagcaatata gtaggtcacc gatcacc
274759PRTArtificial SequenceSynthetic 475Gln Gln Tyr Ser
Arg Ser Pro Ile Thr1 5476357DNAArtificial SequenceSynthetic
476caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc
60acctgcactg tctctggtgg ctccatcaac agtgttactt actactggac ctggatccgc
120cagcacccag ggaggggcct agagtggatt gggtacatca aattcagtgg gagcacctac
180tacaacccgt ccctcaaggg tcgagtcacc atatcagtgg acacgtctaa gaaccaattc
240tcccttaaaa ttaactctgt gactgccgcg gacacggccg tgttttactg tgcgagagct
300tctggaagtc atacttttga tatctggggc caagggacaa tggtcaccgt ctcctca
357477119PRTArtificial SequenceSynthetic 477Gln Val Gln Leu Gln Glu Ser
Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10
15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Asn
Ser Val20 25 30Thr Tyr Tyr Trp Thr Trp
Ile Arg Gln His Pro Gly Arg Gly Leu Glu35 40
45Trp Ile Gly Tyr Ile Lys Phe Ser Gly Ser Thr Tyr Tyr Asn Pro Ser50
55 60Leu Lys Gly Arg Val Thr Ile Ser Val
Asp Thr Ser Lys Asn Gln Phe65 70 75
80Ser Leu Lys Ile Asn Ser Val Thr Ala Ala Asp Thr Ala Val
Phe Tyr85 90 95Cys Ala Arg Ala Ser Gly
Ser His Thr Phe Asp Ile Trp Gly Gln Gly100 105
110Thr Met Val Thr Val Ser Ser11547830DNAArtificial
SequenceSynthetic 478ggtggctcca tcaacagtgt tacttactac
3047910PRTArtificial SequenceSynthetic 479Gly Gly Ser
Ile Asn Ser Val Thr Tyr Tyr1 5
1048021DNAArtificial SequenceSynthetic 480atcaaattca gtgggagcac c
214817PRTArtificial
SequenceSynthetic 481Ile Lys Phe Ser Gly Ser Thr1
548233DNAArtificial SequenceSynthetic 482gcgagagctt ctggaagtca tacttttgat
atc 3348311PRTArtificial
SequenceSynthetic 483Ala Arg Ala Ser Gly Ser His Thr Phe Asp Ile1
5 10484321DNAArtificial SequenceSynthetic
484gccatccgga tgacccagtc tccagccacc ctgtctttgt ctccagggga aagagccacc
60ctctcctgct gggccagtca gagtattagc ggctattttg cctggtatca acagaaacct
120ggccaggctc ccaggctcct catctatgat acatcctaca gggccactga cgtcccagcc
180aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcaacaa cctagagcct
240gaagattttg cagtttatta ctgtcagcag cgtagcgact ggccgctcag cttcggcgga
300gggaccaaac tggagatcaa a
321485107PRTArtificial SequenceSynthetic 485Ala Ile Arg Met Thr Gln Ser
Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10
15Glu Arg Ala Thr Leu Ser Cys Trp Ala Ser Gln Ser Ile Ser
Gly Tyr20 25 30Phe Ala Trp Tyr Gln Gln
Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile35 40
45Tyr Asp Thr Ser Tyr Arg Ala Thr Asp Val Pro Ala Arg Phe Ser Gly50
55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile Asn Asn Leu Glu Pro65 70 75
80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asp Trp
Pro Leu85 90 95Ser Phe Gly Gly Gly Thr
Lys Leu Glu Ile Lys100 10548618DNAArtificial
SequenceSynthetic 486cagagtatta gcggctat
184876PRTArtificial SequenceSynthetic 487Gln Ser Ile Ser
Gly Tyr1 54889DNAArtificial SequenceSynthetic 488gatacatcc
94893PRTArtificial SequenceSynthetic 489Asp Thr Ser149027DNAArtificial
SequenceSynthetic 490cagcagcgta gcgactggcc gctcagc
274919PRTArtificial SequenceSynthetic 491Gln Gln Arg Ser
Asp Trp Pro Leu Ser1 5492357DNAArtificial SequenceSynthetic
492caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc
60acctgcactg tctctggtgg ctccatcaac agtgttactt actactggac ctggatccgc
120cagcacccag ggaggggcct agagtggatt gggtacatca aattcagtgg gagcacctac
180tacaacccgt ccctcaaggg tcgagtcacc atatcagtgg acacgtctaa gaaccaattc
240tcccttaaaa ttaactctgt gactgccgcg gacacggccg tgttttactg tgcgagagct
300tctggaagtc atacttttga tatctggggc caagggacaa tggtcaccgt ctcctca
357493119PRTArtificial SequenceSynthetic 493Gln Val Gln Leu Gln Glu Ser
Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10
15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Asn
Ser Val20 25 30Thr Tyr Tyr Trp Thr Trp
Ile Arg Gln His Pro Gly Arg Gly Leu Glu35 40
45Trp Ile Gly Tyr Ile Lys Phe Ser Gly Ser Thr Tyr Tyr Asn Pro Ser50
55 60Leu Lys Gly Arg Val Thr Ile Ser Val
Asp Thr Ser Lys Asn Gln Phe65 70 75
80Ser Leu Lys Ile Asn Ser Val Thr Ala Ala Asp Thr Ala Val
Phe Tyr85 90 95Cys Ala Arg Ala Ser Gly
Ser His Thr Phe Asp Ile Trp Gly Gln Gly100 105
110Thr Met Val Thr Val Ser Ser11549430DNAArtificial
SequenceSynthetic 494ggtggctcca tcaacagtgt tacttactac
3049510PRTArtificial SequenceSynthetic 495Gly Gly Ser
Ile Asn Ser Val Thr Tyr Tyr1 5
1049621DNAArtificial SequenceSynthetic 496atcaaattca gtgggagcac c
214977PRTArtificial
SequenceSynthetic 497Ile Lys Phe Ser Gly Ser Thr1
549833DNAArtificial SequenceSynthetic 498gcgagagctt ctggaagtca tacttttgat
atc 3349911PRTArtificial
SequenceSynthetic 499Ala Arg Ala Ser Gly Ser His Thr Phe Asp Ile1
5 10500324DNAArtificial SequenceSynthetic
500gatattgtga tgacccagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc
60ctctcctgca gggccagtca gagtgttagc aacagctact tagcctggta ccagcagaaa
120cctggccagg ctcccaggct cctcatctct ggtgcgtcca gcagggtcac tggcatccca
180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag
240cctgaagatt ttggaatgta ttactgtcag cagtatagta ggtcaccgat caccttcggc
300caagggacca aggtggaaat caaa
324501108PRTArtificial SequenceSynthetic 501Asp Ile Val Met Thr Gln Ser
Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10
15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser
Asn Ser20 25 30Tyr Leu Ala Trp Tyr Gln
Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu35 40
45Ile Ser Gly Ala Ser Ser Arg Val Thr Gly Ile Pro Asp Arg Phe Ser50
55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr
Leu Thr Ile Ser Arg Leu Glu65 70 75
80Pro Glu Asp Phe Gly Met Tyr Tyr Cys Gln Gln Tyr Ser Arg
Ser Pro85 90 95Ile Thr Phe Gly Gln Gly
Thr Lys Val Glu Ile Lys100 10550221DNAArtificial
SequenceSynthetic 502cagagtgtta gcaacagcta c
215037PRTArtificial SequenceSynthetic 503Gln Ser Val Ser
Asn Ser Tyr1 55049DNAArtificial SequenceSynthetic
504ggtgcgtcc
95053PRTArtificial SequenceSynthetic 505Gly Ala Ser150627DNAArtificial
SequenceSynthetic 506cagcagtata gtaggtcacc gatcacc
275079PRTArtificial SequenceSynthetic 507Gln Gln Tyr Ser
Arg Ser Pro Ile Thr1 5508357DNAArtificial SequenceSynthetic
508gaggtgcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc
60tcctgcaagg cttctggtta ctcctttacc agctttggtt tcagctgggt gcgacaggcc
120cctggacaag gacttgagtg gctgggatgg atcagcgctt acagtggtga cacagactat
180gcacagaagt tccagggcag agtcaccctg accactgaca catccacgac cactgcctac
240atggagctga ggagcctgag atctgacgac acggccgtct attactgtgc gcgatataac
300tggaacctcc actggttcga cccctggggc cagggaaccc tggtcaccgt ctcctca
357509119PRTArtificial SequenceSynthetic 509Glu Val Gln Leu Val Gln Ser
Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10
15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr
Ser Phe20 25 30Gly Phe Ser Trp Val Arg
Gln Ala Pro Gly Gln Gly Leu Glu Trp Leu35 40
45Gly Trp Ile Ser Ala Tyr Ser Gly Asp Thr Asp Tyr Ala Gln Lys Phe50
55 60Gln Gly Arg Val Thr Leu Thr Thr Asp
Thr Ser Thr Thr Thr Ala Tyr65 70 75
80Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr
Tyr Cys85 90 95Ala Arg Tyr Asn Trp Asn
Leu His Trp Phe Asp Pro Trp Gly Gln Gly100 105
110Thr Leu Val Thr Val Ser Ser11551024DNAArtificial
SequenceSynthetic 510ggttactcct ttaccagctt tggt
245118PRTArtificial SequenceSynthetic 511Gly Tyr Ser Phe
Thr Ser Phe Gly1 551224DNAArtificial SequenceSynthetic
512atcagcgctt acagtggtga caca
245138PRTArtificial SequenceSynthetic 513Ile Ser Ala Tyr Ser Gly Asp Thr1
551436DNAArtificial SequenceSynthetic 514gcgcgatata
actggaacct ccactggttc gacccc
3651512PRTArtificial SequenceSynthetic 515Ala Arg Tyr Asn Trp Asn Leu His
Trp Phe Asp Pro1 5 10516324DNAArtificial
SequenceSynthetic 516gacatccgga tgacccagtc tccaggcatc ctgtctttgt
ctccagggga aagagccacc 60ctctcctgca gggccagtca gaatattaaa agcaactact
tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatcttt ggtacatcca
acagggccac tgccatttca 180gacaggttca gtggcagtgg gtctgggaca gacttccttt
tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcag cagtatggta
actcaccgtg gacgttcggc 300caagggacca aagtggatat caaa
324517108PRTArtificial SequenceSynthetic 517Asp
Ile Arg Met Thr Gln Ser Pro Gly Ile Leu Ser Leu Ser Pro Gly1
5 10 15Glu Arg Ala Thr Leu Ser Cys Arg
Ala Ser Gln Asn Ile Lys Ser Asn20 25
30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu35
40 45Ile Phe Gly Thr Ser Asn Arg Ala Thr Ala
Ile Ser Asp Arg Phe Ser50 55 60Gly Ser
Gly Ser Gly Thr Asp Phe Leu Phe Thr Ile Ser Arg Leu Glu65
70 75 80Pro Glu Asp Phe Ala Val Tyr
Tyr Cys Gln Gln Tyr Gly Asn Ser Pro85 90
95Trp Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys100
10551821DNAArtificial SequenceSynthetic 518cagaatatta aaagcaacta c
215197PRTArtificial
SequenceSynthetic 519Gln Asn Ile Lys Ser Asn Tyr1
55209DNAArtificial SequenceSynthetic 520ggtacatcc
95213PRTArtificial SequenceSynthetic
521Gly Thr Ser152227DNAArtificial SequenceSynthetic 522cagcagtatg
gtaactcacc gtggacg
275239PRTArtificial SequenceSynthetic 523Gln Gln Tyr Gly Asn Ser Pro Trp
Thr1 5524357DNAArtificial SequenceSynthetic 524caggtgcagc
tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg
tctctgatgg ctccatcaac agtgttgaat cctactggac ctggatccgc 120cagcacccag
ggaagggcct ggagtggatt ggatacatca aatacactgg gggcatccac 180tataacccgt
ccctcaagag tcgacttgcc atatcagtgg acacgtcaaa gaaccagttc 240tccctgaaaa
tgagctctgt gactgccgcg gacacggccg tgtattactg tgcgagagca 300cgtggaagtc
atacttttga tgtctggggc caggggacaa tggtcaccgt ctcttca
357525119PRTArtificial SequenceSynthetic 525Gln Val Gln Leu Gln Glu Ser
Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10
15Thr Leu Ser Leu Thr Cys Thr Val Ser Asp Gly Ser Ile Asn
Ser Val20 25 30Glu Ser Tyr Trp Thr Trp
Ile Arg Gln His Pro Gly Lys Gly Leu Glu35 40
45Trp Ile Gly Tyr Ile Lys Tyr Thr Gly Gly Ile His Tyr Asn Pro Ser50
55 60Leu Lys Ser Arg Leu Ala Ile Ser Val
Asp Thr Ser Lys Asn Gln Phe65 70 75
80Ser Leu Lys Met Ser Ser Val Thr Ala Ala Asp Thr Ala Val
Tyr Tyr85 90 95Cys Ala Arg Ala Arg Gly
Ser His Thr Phe Asp Val Trp Gly Gln Gly100 105
110Thr Met Val Thr Val Ser Ser11552630DNAArtificial
SequenceSynthetic 526gatggctcca tcaacagtgt tgaatcctac
3052710PRTArtificial SequenceSynthetic 527Asp Gly Ser
Ile Asn Ser Val Glu Ser Tyr1 5
1052821DNAArtificial SequenceSynthetic 528atcaaataca ctgggggcat c
215297PRTArtificial
SequenceSynthetic 529Ile Lys Tyr Thr Gly Gly Ile1
553033DNAArtificial SequenceSynthetic 530gcgagagcac gtggaagtca tacttttgat
gtc 3353111PRTArtificial
SequenceSynthetic 531Ala Arg Ala Arg Gly Ser His Thr Phe Asp Val1
5 10532324DNAArtificial SequenceSynthetic
532gaaattgtgc tgactcagtc tccaggcacc ctgtcttggt ctccagggga aagagccacc
60ctctcctgca gggccagtca gagtattagc agtaactact tagcctggta ccagcagaaa
120cctggccagg ctcccagact cctcatttat ggtgcatcca gcagggtcac tggcatccca
180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag
240cctgaagatt ttgcactgta ttattgtcag cagtatagta ggtcaccgat caccttcggc
300caagggacca aagtggatat caaa
324533108PRTArtificial SequenceSynthetic 533Glu Ile Val Leu Thr Gln Ser
Pro Gly Thr Leu Ser Trp Ser Pro Gly1 5 10
15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser
Ser Asn20 25 30Tyr Leu Ala Trp Tyr Gln
Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu35 40
45Ile Tyr Gly Ala Ser Ser Arg Val Thr Gly Ile Pro Asp Arg Phe Ser50
55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr
Leu Thr Ile Ser Arg Leu Glu65 70 75
80Pro Glu Asp Phe Ala Leu Tyr Tyr Cys Gln Gln Tyr Ser Arg
Ser Pro85 90 95Ile Thr Phe Gly Gln Gly
Thr Lys Val Asp Ile Lys100 10553421DNAArtificial
SequenceSynthetic 534cagagtatta gcagtaacta c
215357PRTArtificial SequenceSynthetic 535Gln Ser Ile Ser
Ser Asn Tyr1 55369DNAArtificial SequenceSynthetic
536ggtgcatcc
95373PRTArtificial SequenceSynthetic 537Gly Ala Ser153827DNAArtificial
SequenceSynthetic 538cagcagtata gtaggtcacc gatcacc
275399PRTArtificial SequenceSynthetic 539Gln Gln Tyr Ser
Arg Ser Pro Ile Thr1 5540360DNAArtificial SequenceSynthetic
540caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc
60acctgcactg tctctggtgg ctccgtcagc agtggtaatt actactggag ctggatccgc
120cagcacccag ggaagggcct ggagtggttt gggtacatca aaaacagtgg gggcacctac
180tacaacccgt ccctcaagag tcgaattacc atatcagtag acacgtctaa gaaccacttc
240tccctgaggc tgagctctat gacggccgcg gacacggccg tgtattactg tgcgagagct
300ggttcgggga gtcactactt tgactactgg ggccagggaa ccctggtcac cgtctcctca
360541120PRTArtificial SequenceSynthetic 541Gln Val Gln Leu Gln Glu Ser
Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10
15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser
Ser Gly20 25 30Asn Tyr Tyr Trp Ser Trp
Ile Arg Gln His Pro Gly Lys Gly Leu Glu35 40
45Trp Phe Gly Tyr Ile Lys Asn Ser Gly Gly Thr Tyr Tyr Asn Pro Ser50
55 60Leu Lys Ser Arg Ile Thr Ile Ser Val
Asp Thr Ser Lys Asn His Phe65 70 75
80Ser Leu Arg Leu Ser Ser Met Thr Ala Ala Asp Thr Ala Val
Tyr Tyr85 90 95Cys Ala Arg Ala Gly Ser
Gly Ser His Tyr Phe Asp Tyr Trp Gly Gln100 105
110Gly Thr Leu Val Thr Val Ser Ser115
12054230DNAArtificial SequenceSynthetic 542ggtggctccg tcagcagtgg
taattactac 3054310PRTArtificial
SequenceSynthetic 543Gly Gly Ser Val Ser Ser Gly Asn Tyr Tyr1
5 1054421DNAArtificial SequenceSynthetic 544atcaaaaaca
gtgggggcac c
215457PRTArtificial SequenceSynthetic 545Ile Lys Asn Ser Gly Gly Thr1
554636DNAArtificial SequenceSynthetic 546gcgagagctg gttcggggag
tcactacttt gactac 3654712PRTArtificial
SequenceSynthetic 547Ala Arg Ala Gly Ser Gly Ser His Tyr Phe Asp Tyr1
5 10548324DNAArtificial SequenceSynthetic
548gaaacgacac tcacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc
60ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa
120cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca
180gacaggctca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag
240cctgaagatt gtgcagtgta ttactgtcag cagtatggtt actcaccgat caccttcggc
300caagggacca aggtggaaat caaa
324549108PRTArtificial SequenceSynthetic 549Glu Thr Thr Leu Thr Gln Ser
Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10
15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser
Ser Ser20 25 30Tyr Leu Ala Trp Tyr Gln
Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu35 40
45Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Leu Ser50
55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr
Leu Thr Ile Ser Arg Leu Glu65 70 75
80Pro Glu Asp Cys Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Tyr
Ser Pro85 90 95Ile Thr Phe Gly Gln Gly
Thr Lys Val Glu Ile Lys100 10555021DNAArtificial
SequenceSynthetic 550cagagtgtta gcagcagcta c
215517PRTArtificial SequenceSynthetic 551Gln Ser Val Ser
Ser Ser Tyr1 55529DNAArtificial SequenceSynthetic
552ggtgcatcc
95533PRTArtificial SequenceSynthetic 553Gly Ala Ser155427DNAArtificial
SequenceSynthetic 554cagcagtatg gttactcacc gatcacc
275559PRTArtificial SequenceSynthetic 555Gln Gln Tyr Gly
Tyr Ser Pro Ile Thr1 5556369DNAArtificial SequenceSynthetic
556gaagtgcagc tggtgcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc
60tcctgtacag cgtctggatt caccttcagt agctatgcca tgtactgggt ccgccaggct
120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtaa taaaaactat
180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacactgtat
240ctgcaagtga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatcac
300gattttttga gtggttatga ggggtggttc gacccctggg gccagggaac cctggtcacc
360gtctcctca
369557123PRTArtificial SequenceSynthetic 557Glu Val Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10
15Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser
Ser Tyr20 25 30Ala Met Tyr Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val35 40
45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Asn Tyr Ala Asp Ser Val50
55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Val Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys85 90 95Ala Arg Asp His Asp Phe
Leu Ser Gly Tyr Glu Gly Trp Phe Asp Pro100 105
110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser115
12055824DNAArtificial SequenceSynthetic 558ggattcacct tcagtagcta tgcc
245598PRTArtificial
SequenceSynthetic 559Gly Phe Thr Phe Ser Ser Tyr Ala1
556024DNAArtificial SequenceSynthetic 560atatggtatg atggaagtaa taaa
245618PRTArtificial
SequenceSynthetic 561Ile Trp Tyr Asp Gly Ser Asn Lys1
556248DNAArtificial SequenceSynthetic 562gcgagagatc acgatttttt gagtggttat
gaggggtggt tcgacccc 4856316PRTArtificial
SequenceSynthetic 563Ala Arg Asp His Asp Phe Leu Ser Gly Tyr Glu Gly Trp
Phe Asp Pro1 5 10
15564321DNAArtificial SequenceSynthetic 564gaaattgtgc tgactcagtc
tccagccacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca
gagtgttagt agctacttag cctggtacca acagaaacct 120ggccaggctc ccaggctcct
catctatgat gcatccaaca gggccactgg catcccagcc 180aggttcagtg gcagtgggtc
tgggacagac ttcactctca ccatcagtag cctagagcct 240gaagattttg cagtttatta
ctgtcagcaa cgtagcaact ggcctcccac tttcggcgga 300gggaccaaag tggatatcaa a
321565107PRTArtificial
SequenceSynthetic 565Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu
Ser Pro Gly1 5 10 15Glu
Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr20
25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala
Pro Arg Leu Leu Ile35 40 45Tyr Asp Ala
Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly50 55
60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
Leu Glu Pro65 70 75
80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro85
90 95Thr Phe Gly Gly Gly Thr Lys Val Asp Ile
Lys100 10556618DNAArtificial SequenceSynthetic
566cagagtgtta gtagctac
185676PRTArtificial SequenceSynthetic 567Gln Ser Val Ser Ser Tyr1
55689DNAArtificial SequenceSynthetic 568gatgcatcc
95693PRTArtificial
SequenceSynthetic 569Asp Ala Ser157027DNAArtificial SequenceSynthetic
570cagcaacgta gcaactggcc tcccact
275719PRTArtificial SequenceSynthetic 571Gln Gln Arg Ser Asn Trp Pro Pro
Thr1 5572375DNAArtificial SequenceSynthetic 572gaggtgcagc
tggtgcagtc tggagctgaa gtgaagaacc ctggggcctc agttagggtc 60tcctgcaagg
cttctggtta cacctttacc acctatggta tcacctgggt gcgacagggc 120cctggacaag
ggcttgagtg gatgggatgg atcagcgctt tcaatggtga cacaaacttt 180gcacagaacc
tccagaacag agtcaccctg accacagaca catccactag cacagcctat 240atggaactga
ggagcctgag atctgacgac acggccgttt attactgtgc gagaggggga 300ggagctcgtc
cggggaactt cttcttctac ggtatggacg tctggggcca ggggaccacg 360gtcaccgtct
cctca
375573125PRTArtificial SequenceSynthetic 573Glu Val Gln Leu Val Gln Ser
Gly Ala Glu Val Lys Asn Pro Gly Ala1 5 10
15Ser Val Arg Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
Thr Tyr20 25 30Gly Ile Thr Trp Val Arg
Gln Gly Pro Gly Gln Gly Leu Glu Trp Met35 40
45Gly Trp Ile Ser Ala Phe Asn Gly Asp Thr Asn Phe Ala Gln Asn Leu50
55 60Gln Asn Arg Val Thr Leu Thr Thr Asp
Thr Ser Thr Ser Thr Ala Tyr65 70 75
80Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr
Tyr Cys85 90 95Ala Arg Gly Gly Gly Ala
Arg Pro Gly Asn Phe Phe Phe Tyr Gly Met100 105
110Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser115
120 12557424DNAArtificial SequenceSynthetic
574ggttacacct ttaccaccta tggt
245758PRTArtificial SequenceSynthetic 575Gly Tyr Thr Phe Thr Thr Tyr Gly1
557624DNAArtificial SequenceSynthetic 576atcagcgctt
tcaatggtga caca
245778PRTArtificial SequenceSynthetic 577Ile Ser Ala Phe Asn Gly Asp Thr1
557854DNAArtificial SequenceSynthetic 578gcgagagggg
gaggagctcg tccggggaac ttcttcttct acggtatgga cgtc
5457918PRTArtificial SequenceSynthetic 579Ala Arg Gly Gly Gly Ala Arg Pro
Gly Asn Phe Phe Phe Tyr Gly Met1 5 10
15Asp Val580321DNAArtificial SequenceSynthetic 580gatgttgtga
tgactcagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgta
gggccagtca gagttttgcc agctacttag cctggtacca acagaaacct 120ggccaggctc
ccaggctcct catctatgat acctcctaca gggccactgg cgtcccagcc 180aggttcagtg
gcagtgggtc tgggacagac ttcactctca acatcagcaa cctggagcct 240gaagattttg
cagtttatta ctgtcagcaa cgtggcaact ggccgctcac tttcggcgga 300gggaccaagg
tggaaatcaa a
321581107PRTArtificial SequenceSynthetic 581Asp Val Val Met Thr Gln Ser
Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10
15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Phe Ala
Ser Tyr20 25 30Leu Ala Trp Tyr Gln Gln
Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile35 40
45Tyr Asp Thr Ser Tyr Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Gly50
55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu
Asn Ile Ser Asn Leu Glu Pro65 70 75
80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Gly Asn Trp
Pro Leu85 90 95Thr Phe Gly Gly Gly Thr
Lys Val Glu Ile Lys100 10558218DNAArtificial
SequenceSynthetic 582cagagttttg ccagctac
185836PRTArtificial SequenceSynthetic 583Gln Ser Phe Ala
Ser Tyr1 55849DNAArtificial SequenceSynthetic 584gatacctcc
95853PRTArtificial SequenceSynthetic 585Asp Thr Ser158627DNAArtificial
SequenceSynthetic 586cagcaacgtg gcaactggcc gctcact
275879PRTArtificial SequenceSynthetic 587Gln Gln Arg Gly
Asn Trp Pro Leu Thr1 5588357DNAArtificial SequenceSynthetic
588caggtgcagc tggtgcagtc tggaactgag gtgaagaagc ctggggcctc agtgaaggtc
60tcctgcaagg cttctggtta cacctttagc tacaatggtg tcacttgggt acgacaggcc
120cctggacaag ggcttgagtg gatgggatgg atcagcgctt acgatggtaa cacagactat
180gcacagaagt tccaagacag aatcaccatg accacagaca catccacgag tacagcctac
240atggaactga ggagccttag atctgacgac acggccgtct attactgtgc gaggtatagt
300tggaacaacc actggttcga cccctggggc cagggaaccc tggtcaccgt ctcctca
357589119PRTArtificial SequenceSynthetic 589Gln Val Gln Leu Val Gln Ser
Gly Thr Glu Val Lys Lys Pro Gly Ala1 5 10
15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser
Tyr Asn20 25 30Gly Val Thr Trp Val Arg
Gln Ala Pro Gly Gln Gly Leu Glu Trp Met35 40
45Gly Trp Ile Ser Ala Tyr Asp Gly Asn Thr Asp Tyr Ala Gln Lys Phe50
55 60Gln Asp Arg Ile Thr Met Thr Thr Asp
Thr Ser Thr Ser Thr Ala Tyr65 70 75
80Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr
Tyr Cys85 90 95Ala Arg Tyr Ser Trp Asn
Asn His Trp Phe Asp Pro Trp Gly Gln Gly100 105
110Thr Leu Val Thr Val Ser Ser11559024DNAArtificial
SequenceSynthetic 590ggttacacct ttagctacaa tggt
245918PRTArtificial SequenceSynthetic 591Gly Tyr Thr Phe
Ser Tyr Asn Gly1 559224DNAArtificial SequenceSynthetic
592atcagcgctt acgatggtaa caca
245938PRTArtificial SequenceSynthetic 593Ile Ser Ala Tyr Asp Gly Asn Thr1
559436DNAArtificial SequenceSynthetic 594gcgaggtata
gttggaacaa ccactggttc gacccc
3659512PRTArtificial SequenceSynthetic 595Ala Arg Tyr Ser Trp Asn Asn His
Trp Phe Asp Pro1 5 10596324DNAArtificial
SequenceSynthetic 596gatattgtga tgactcagtc tccaggcacc ctgtctttgt
ctccaggaga cggggccacc 60ctctcctgca gggccagtca gagtgtttcc ggcagctact
tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatttat ggtgcatcca
acagggccac tggcatccca 180gacaggttca ctggcagtgg gtctgggaca gacttcactc
tcaccatcag cagactggag 240cctgaagatt ttgcagtgta tttctgtcag cagagtgctt
tctcaccgtg gacgttcggc 300caagggacca agctggagat caaa
324597108PRTArtificial SequenceSynthetic 597Asp
Ile Val Met Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1
5 10 15Asp Gly Ala Thr Leu Ser Cys Arg
Ala Ser Gln Ser Val Ser Gly Ser20 25
30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu35
40 45Ile Tyr Gly Ala Ser Asn Arg Ala Thr Gly
Ile Pro Asp Arg Phe Thr50 55 60Gly Ser
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65
70 75 80Pro Glu Asp Phe Ala Val Tyr
Phe Cys Gln Gln Ser Ala Phe Ser Pro85 90
95Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys100
10559821DNAArtificial SequenceSynthetic 598cagagtgttt ccggcagcta c
215997PRTArtificial
SequenceSynthetic 599Gln Ser Val Ser Gly Ser Tyr1
56009DNAArtificial SequenceSynthetic 600ggtgcatcc
96013PRTArtificial SequenceSynthetic
601Gly Ala Ser160227DNAArtificial SequenceSynthetic 602cagcagagtg
ctttctcacc gtggacg
276039PRTArtificial SequenceSynthetic 603Gln Gln Ser Ala Phe Ser Pro Trp
Thr1 5604351DNAArtificial SequenceSynthetic 604gaagtgcagc
tggtgcagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60tcctgtgcag
cctctggatt caccttcagt atgtacgaca tgcactgggt ccgccaaact 120ataggaaaag
gtctggagtg ggtctcagca attggtactg ctggtgacac atactatcca 180ggctccgtga
agggccgatt caccatctcc agagaaaatg ccaagaactc cttgtttctt 240caaatgaaca
gcctgagagc cggggacacg gctgtttatt actgtgtaag atccgggact 300acagagtggt
tcgacccctg gggccaggga accccggtca ctgtctcctc a
351605117PRTArtificial SequenceSynthetic 605Glu Val Gln Leu Val Gln Ser
Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10
15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
Met Tyr20 25 30Asp Met His Trp Val Arg
Gln Thr Ile Gly Lys Gly Leu Glu Trp Val35 40
45Ser Ala Ile Gly Thr Ala Gly Asp Thr Tyr Tyr Pro Gly Ser Val Lys50
55 60Gly Arg Phe Thr Ile Ser Arg Glu Asn
Ala Lys Asn Ser Leu Phe Leu65 70 75
80Gln Met Asn Ser Leu Arg Ala Gly Asp Thr Ala Val Tyr Tyr
Cys Val85 90 95Arg Ser Gly Thr Thr Glu
Trp Phe Asp Pro Trp Gly Gln Gly Thr Pro100 105
110Val Thr Val Ser Ser11560624DNAArtificial SequenceSynthetic
606ggattcacct tcagtatgta cgac
246078PRTArtificial SequenceSynthetic 607Gly Phe Thr Phe Ser Met Tyr Asp1
560821DNAArtificial SequenceSynthetic 608attggtactg
ctggtgacac a
216097PRTArtificial SequenceSynthetic 609Ile Gly Thr Ala Gly Asp Thr1
561033DNAArtificial SequenceSynthetic 610gtaagatccg ggactacaga
gtggttcgac ccc 3361111PRTArtificial
SequenceSynthetic 611Val Arg Ser Gly Thr Thr Glu Trp Phe Asp Pro1
5 10612321DNAArtificial SequenceSynthetic
612gacatccggt tgacccagtc tccatcttcc gtgtctgcat ctgtgggaga cagagtcacc
60atcacttgtc ggacgagtca gggtattagt agctggttag cctggtatca gcagaaacca
120ggaaaagccc ctaacctcct gatctatgct gcatccagtt tacaaagtgg ggtcccatca
180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct
240gaagattttg caacttacta ttgtctacag gctaacagtt tcccgtacac ttttggccag
300gggaccaagg tggagatcaa a
321613107PRTArtificial SequenceSynthetic 613Asp Ile Arg Leu Thr Gln Ser
Pro Ser Ser Val Ser Ala Ser Val Gly1 5 10
15Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Gln Gly Ile Ser
Ser Trp20 25 30Leu Ala Trp Tyr Gln Gln
Lys Pro Gly Lys Ala Pro Asn Leu Leu Ile35 40
45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly50
55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro65 70 75
80Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Ala Asn Ser Phe
Pro Tyr85 90 95Thr Phe Gly Gln Gly Thr
Lys Val Glu Ile Lys100 10561418DNAArtificial
SequenceSynthetic 614cagggtatta gtagctgg
186156PRTArtificial SequenceSynthetic 615Gln Gly Ile Ser
Ser Trp1 56169DNAArtificial SequenceSynthetic 616gctgcatcc
96173PRTArtificial SequenceSynthetic 617Ala Ala Ser161827DNAArtificial
SequenceSynthetic 618ctacaggcta acagtttccc gtacact
276199PRTArtificial SequenceSynthetic 619Leu Gln Ala Asn
Ser Phe Pro Tyr Thr1 5620369DNAArtificial SequenceSynthetic
620caggtccagc tggtgcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc
60tcctgtgcag cgtctggatt caccttcagt agttatggca tgcactgggt ccgccaggct
120ccaggcaagg ggctggagtg ggtggcagtt ttatggtatg atggaagtaa taaaaactat
180gtagactccg tgaagggccg attcaccatc tcaagagaca attccaagaa cacgctttat
240ctgcaaatga acagcctgag agccgaggac acggctgtgt attattgtgc gagagatcat
300gattttagga gtggttatga ggggtggttc gacccctggg gccagggaac cctggtcacc
360gtctcctca
369621123PRTArtificial SequenceSynthetic 621Gln Val Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10
15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
Ser Tyr20 25 30Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val35 40
45Ala Val Leu Trp Tyr Asp Gly Ser Asn Lys Asn Tyr Val Asp Ser Val50
55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys85 90 95Ala Arg Asp His Asp Phe
Arg Ser Gly Tyr Glu Gly Trp Phe Asp Pro100 105
110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser115
12062224DNAArtificial SequenceSynthetic 622ggattcacct tcagtagtta tggc
246238PRTArtificial
SequenceSynthetic 623Gly Phe Thr Phe Ser Ser Tyr Gly1
562424DNAArtificial SequenceSynthetic 624ttatggtatg atggaagtaa taaa
246258PRTArtificial
SequenceSynthetic 625Leu Trp Tyr Asp Gly Ser Asn Lys1
562648DNAArtificial SequenceSynthetic 626gcgagagatc atgattttag gagtggttat
gaggggtggt tcgacccc 4862716PRTArtificial
SequenceSynthetic 627Ala Arg Asp His Asp Phe Arg Ser Gly Tyr Glu Gly Trp
Phe Asp Pro1 5 10
15628321DNAArtificial SequenceSynthetic 628gaaattgtgc tgacgcagtc
tccagccacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca
gagtgttcgc agctacttag cctggtacca acagaaacct 120ggccaggctc ccaggctcct
catctatgat gcatccaaca gggccactgg catcccagcc 180aggttcagtg gcagtgggtc
tgggacagac ttcactctca ccatcagcag cctagagcct 240gaagattttg cagtttatta
ctgtcaacac cgtagcaact ggcctcccac tttcggcgga 300gggaccaagg tggaaatcaa a
321629107PRTArtificial
SequenceSynthetic 629Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu
Ser Pro Gly1 5 10 15Glu
Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Arg Ser Tyr20
25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala
Pro Arg Leu Leu Ile35 40 45Tyr Asp Ala
Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly50 55
60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
Leu Glu Pro65 70 75
80Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Arg Ser Asn Trp Pro Pro85
90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
Lys100 10563018DNAArtificial SequenceSynthetic
630cagagtgttc gcagctac
186316PRTArtificial SequenceSynthetic 631Gln Ser Val Arg Ser Tyr1
56329DNAArtificial SequenceSynthetic 632gatgcatcc
96333PRTArtificial
SequenceSynthetic 633Asp Ala Ser163427DNAArtificial SequenceSynthetic
634caacaccgta gcaactggcc tcccact
276359PRTArtificial SequenceSynthetic 635Gln His Arg Ser Asn Trp Pro Pro
Thr1 5636354DNAArtificial SequenceSynthetic 636caggtcacct
tgaaggagtc gggcccagga ctggtgaagt cttcggagac cctgtccctc 60acttgcactg
tctctactgg ctccatcagc agtagtagtt actactgggc ctggatccgc 120cagcccccag
ggaagggact ggagtggatt gggagtatct attatagtgg gagtaaattc 180tacagcccgt
ccctcaagag tcgagtcacc atatacgttg acacgtccaa gaatcagttc 240tccctgcaac
tgagctcggt gaccgccgca gacacggctg tatattactg tgcgagacag 300gtcggtgcaa
tctttgacta ctggggccag ggaaccctgg tcaccgtctc ctca
354637118PRTArtificial SequenceSynthetic 637Gln Val Thr Leu Lys Glu Ser
Gly Pro Gly Leu Val Lys Ser Ser Glu1 5 10
15Thr Leu Ser Leu Thr Cys Thr Val Ser Thr Gly Ser Ile Ser
Ser Ser20 25 30Ser Tyr Tyr Trp Ala Trp
Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu35 40
45Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Lys Phe Tyr Ser Pro Ser50
55 60Leu Lys Ser Arg Val Thr Ile Tyr Val
Asp Thr Ser Lys Asn Gln Phe65 70 75
80Ser Leu Gln Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val
Tyr Tyr85 90 95Cys Ala Arg Gln Val Gly
Ala Ile Phe Asp Tyr Trp Gly Gln Gly Thr100 105
110Leu Val Thr Val Ser Ser11563830DNAArtificial SequenceSynthetic
638actggctcca tcagcagtag tagttactac
3063910PRTArtificial SequenceSynthetic 639Thr Gly Ser Ile Ser Ser Ser Ser
Tyr Tyr1 5 1064021DNAArtificial
SequenceSynthetic 640atctattata gtgggagtaa a
216417PRTArtificial SequenceSynthetic 641Ile Tyr Tyr Ser
Gly Ser Lys1 564230DNAArtificial SequenceSynthetic
642gcgagacagg tcggtgcaat ctttgactac
3064310PRTArtificial SequenceSynthetic 643Ala Arg Gln Val Gly Ala Ile Phe
Asp Tyr1 5 10644321DNAArtificial
SequenceSynthetic 644gccatccggt tgacccagtc tccttccacc ctgtctgcat
ctgtaggaga cagagtcacc 60atctcttgcc gggccagtca gagtattagt agttggttgg
cctggtatca gcacaaacca 120gggaaagccc ctaaactcct gctctataag gcgtctagtt
tagaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagag ttcactctca
ccatcagcag cctgcagcct 240gatgattttg caacttatta ctgccaacag tataatagtt
attctcggac gttcggccaa 300gggaccaagg tggagatcaa a
321645107PRTArtificial SequenceSynthetic 645Ala
Ile Arg Leu Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly1
5 10 15Asp Arg Val Thr Ile Ser Cys Arg
Ala Ser Gln Ser Ile Ser Ser Trp20 25
30Leu Ala Trp Tyr Gln His Lys Pro Gly Lys Ala Pro Lys Leu Leu Leu35
40 45Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val
Pro Ser Arg Phe Ser Gly50 55 60Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65
70 75 80Asp Asp Phe Ala Thr Tyr Tyr
Cys Gln Gln Tyr Asn Ser Tyr Ser Arg85 90
95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys100
10564618DNAArtificial SequenceSynthetic 646cagagtatta gtagttgg
186476PRTArtificial
SequenceSynthetic 647Gln Ser Ile Ser Ser Trp1
56489DNAArtificial SequenceSynthetic 648aaggcgtct
96493PRTArtificial SequenceSynthetic
649Lys Ala Ser165027DNAArtificial SequenceSynthetic 650caacagtata
atagttattc tcggacg
276519PRTArtificial SequenceSynthetic 651Gln Gln Tyr Asn Ser Tyr Ser Arg
Thr1 5652372DNAArtificial SequenceSynthetic 652gaggtgcagc
tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg
cctctggtta cacctttaac atctatggta tcagctgggt acgacaggcc 120cctggacaag
ggcttgagtg gatgggatgg atcagcgctt acaatggtaa cacaaactat 180gcacagaaac
tccagggcag agtcaccatg accacagaaa catccacgac cacagcctac 240atggagttga
ggagcctgag atctgacgac acggccgtgt attactgtgc gagagattct 300gattggggaa
ctccctacca ctactacggt atggacgtct ggggccaagg gaccacggtc 360accgtctcct
ca
372653124PRTArtificial SequenceSynthetic 653Glu Val Gln Leu Val Gln Ser
Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10
15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Asn
Ile Tyr20 25 30Gly Ile Ser Trp Val Arg
Gln Ala Pro Gly Gln Gly Leu Glu Trp Met35 40
45Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu50
55 60Gln Gly Arg Val Thr Met Thr Thr Glu
Thr Ser Thr Thr Thr Ala Tyr65 70 75
80Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr
Tyr Cys85 90 95Ala Arg Asp Ser Asp Trp
Gly Thr Pro Tyr His Tyr Tyr Gly Met Asp100 105
110Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser115
12065424DNAArtificial SequenceSynthetic 654ggttacacct ttaacatcta tggt
246558PRTArtificial
SequenceSynthetic 655Gly Tyr Thr Phe Asn Ile Tyr Gly1
565624DNAArtificial SequenceSynthetic 656atcagcgctt acaatggtaa caca
246578PRTArtificial
SequenceSynthetic 657Ile Ser Ala Tyr Asn Gly Asn Thr1
565851DNAArtificial SequenceSynthetic 658gcgagagatt ctgattgggg aactccctac
cactactacg gtatggacgt c 5165917PRTArtificial
SequenceSynthetic 659Ala Arg Asp Ser Asp Trp Gly Thr Pro Tyr His Tyr Tyr
Gly Met Asp1 5 10
15Val660339DNAArtificial SequenceSynthetic 660gatattgtga tgacccagtc
tccagactcc ctggctgtgt ctctgggcga gagggccacc 60atcaactgca agtccagcca
gaatatttta tacacctcca acaataagaa ctacttagct 120tggtaccagc agaaaccagg
acagcctcct aagctgctca tttactgggc atttacccgg 180aaatccgggg tccctgaccg
attcagtggc agcgggtctg ggacagattt cactctcacc 240atcagcagcc tgcaggctga
agatgtggca gtttattact gtcagcaata ttataatact 300cctcggacgt tcggccaagg
gaccaaagtg gatatcaaa 339661113PRTArtificial
SequenceSynthetic 661Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val
Ser Leu Gly1 5 10 15Glu
Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Asn Ile Leu Tyr Thr20
25 30Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln
Gln Lys Pro Gly Gln35 40 45Pro Pro Lys
Leu Leu Ile Tyr Trp Ala Phe Thr Arg Lys Ser Gly Val50 55
60Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
Thr Leu Thr65 70 75
80Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln85
90 95Tyr Tyr Asn Thr Pro Arg Thr Phe Gly Gln
Gly Thr Lys Val Asp Ile100 105
110Lys66236DNAArtificial SequenceSynthetic 662cagaatattt tatacacctc
caacaataag aactac 3666312PRTArtificial
SequenceSynthetic 663Gln Asn Ile Leu Tyr Thr Ser Asn Asn Lys Asn Tyr1
5 106649DNAArtificial SequenceSynthetic
664tgggcattt
96653PRTArtificial SequenceSynthetic 665Trp Ala Phe166627DNAArtificial
SequenceSynthetic 666cagcaatatt ataatactcc tcggacg
276679PRTArtificial SequenceSynthetic 667Gln Gln Tyr Tyr
Asn Thr Pro Arg Thr1 5668357DNAArtificial SequenceSynthetic
668cagatcacct tgaaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc
60acctgcactg tctctgatgg ctccatcaac agtggtggtt cctactggag ctggatccgc
120cagcacccgg ggaagggcct ggagtggatt gggtacatca aatacagtgg gggcgtccac
180tataacccgt ccctcaagag tcgaatcacc atatcagtgg acacgtctaa gaaccatttc
240tccctgaaaa tgacctctgt gactgccgcg gacacggccg tgtatttctg tgcgagagca
300cctggaagtc acacttttga tatctggggc caggggacaa tggtcaccgt ctcttca
357669119PRTArtificial SequenceSynthetic 669Gln Ile Thr Leu Lys Glu Ser
Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10
15Thr Leu Ser Leu Thr Cys Thr Val Ser Asp Gly Ser Ile Asn
Ser Gly20 25 30Gly Ser Tyr Trp Ser Trp
Ile Arg Gln His Pro Gly Lys Gly Leu Glu35 40
45Trp Ile Gly Tyr Ile Lys Tyr Ser Gly Gly Val His Tyr Asn Pro Ser50
55 60Leu Lys Ser Arg Ile Thr Ile Ser Val
Asp Thr Ser Lys Asn His Phe65 70 75
80Ser Leu Lys Met Thr Ser Val Thr Ala Ala Asp Thr Ala Val
Tyr Phe85 90 95Cys Ala Arg Ala Pro Gly
Ser His Thr Phe Asp Ile Trp Gly Gln Gly100 105
110Thr Met Val Thr Val Ser Ser11567030DNAArtificial
SequenceSynthetic 670gatggctcca tcaacagtgg tggttcctac
3067110PRTArtificial SequenceSynthetic 671Asp Gly Ser
Ile Asn Ser Gly Gly Ser Tyr1 5
1067221DNAArtificial SequenceSynthetic 672atcaaataca gtgggggcgt c
216737PRTArtificial
SequenceSynthetic 673Ile Lys Tyr Ser Gly Gly Val1
567433DNAArtificial SequenceSynthetic 674gcgagagcac ctggaagtca cacttttgat
atc 3367511PRTArtificial
SequenceSynthetic 675Ala Arg Ala Pro Gly Ser His Thr Phe Asp Ile1
5 10676324DNAArtificial SequenceSynthetic
676gatattgtga tgactcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc
60ctctcctgca gggccagtca gagtgttagc aacaactact tagcctggta ccagcagaaa
120cctggccagg ctcccagact cctcatctat ggtacatcca atagggtcag tggcatccca
180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag
240cctgaagatt ttgaactata ttattgtcag cagtatagta ggtcaccgat caccttcggc
300caagggacac gactggagat taaa
324677108PRTArtificial SequenceSynthetic 677Asp Ile Val Met Thr Gln Ser
Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10
15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser
Asn Asn20 25 30Tyr Leu Ala Trp Tyr Gln
Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu35 40
45Ile Tyr Gly Thr Ser Asn Arg Val Ser Gly Ile Pro Asp Arg Phe Ser50
55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr
Leu Thr Ile Ser Arg Leu Glu65 70 75
80Pro Glu Asp Phe Glu Leu Tyr Tyr Cys Gln Gln Tyr Ser Arg
Ser Pro85 90 95Ile Thr Phe Gly Gln Gly
Thr Arg Leu Glu Ile Lys100 10567821DNAArtificial
SequenceSynthetic 678cagagtgtta gcaacaacta c
216797PRTArtificial SequenceSynthetic 679Gln Ser Val Ser
Asn Asn Tyr1 56809DNAArtificial SequenceSynthetic
680ggtacatcc
96813PRTArtificial SequenceSynthetic 681Gly Thr Ser168227DNAArtificial
SequenceSynthetic 682cagcagtata gtaggtcacc gatcacc
276839PRTArtificial SequenceSynthetic 683Gln Gln Tyr Ser
Arg Ser Pro Ile Thr1 5684360DNAArtificial SequenceSynthetic
684gaggtgcagc tggtgcagtc tgggggaggc ttggtacaac ctggggggtc cctgagactc
60tcctgtgcag cctctggatt cacctttaac aactttgcca tgacctgggt ccgccaggct
120ccagggaagg gcctggagtg ggtctcaact attagtggta gtggcgttga cacatactgc
180gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacactgtat
240ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagatggc
300gccttctata gtggctacga acactactgg ggccagggaa caatggtcac cgtctcctca
360685120PRTArtificial SequenceSynthetic 685Glu Val Gln Leu Val Gln Ser
Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10
15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn
Asn Phe20 25 30Ala Met Thr Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val35 40
45Ser Thr Ile Ser Gly Ser Gly Val Asp Thr Tyr Cys Ala Asp Ser Val50
55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys85 90 95Ala Lys Asp Gly Ala Phe
Tyr Ser Gly Tyr Glu His Tyr Trp Gly Gln100 105
110Gly Thr Met Val Thr Val Ser Ser115
12068624DNAArtificial SequenceSynthetic 686ggattcacct ttaacaactt tgcc
246878PRTArtificial
SequenceSynthetic 687Gly Phe Thr Phe Asn Asn Phe Ala1
568824DNAArtificial SequenceSynthetic 688attagtggta gtggcgttga caca
246898PRTArtificial
SequenceSynthetic 689Ile Ser Gly Ser Gly Val Asp Thr1
569039DNAArtificial SequenceSynthetic 690gcgaaagatg gcgccttcta tagtggctac
gaacactac 3969113PRTArtificial
SequenceSynthetic 691Ala Lys Asp Gly Ala Phe Tyr Ser Gly Tyr Glu His Tyr1
5 10692324DNAArtificial SequenceSynthetic
692gaaacgacac tcacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc
60ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa
120cctggccagg ctcccaggct cctcatctat ggtacatcca acagggcctc tggcatccca
180gacaggctca ttggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag
240tctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcacctcg gacgttcggc
300caagggacca aagtggatat caaa
324693108PRTArtificial SequenceSynthetic 693Glu Thr Thr Leu Thr Gln Ser
Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10
15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser
Ser Ser20 25 30Tyr Leu Ala Trp Tyr Gln
Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu35 40
45Ile Tyr Gly Thr Ser Asn Arg Ala Ser Gly Ile Pro Asp Arg Leu Ile50
55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr
Leu Thr Ile Ser Arg Leu Glu65 70 75
80Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser
Ser Pro85 90 95Arg Thr Phe Gly Gln Gly
Thr Lys Val Asp Ile Lys100 10569421DNAArtificial
SequenceSynthetic 694cagagtgtta gcagcagcta c
216957PRTArtificial SequenceSynthetic 695Gln Ser Val Ser
Ser Ser Tyr1 56969DNAArtificial SequenceSynthetic
696ggtacatcc
96973PRTArtificial SequenceSynthetic 697Gly Thr Ser169827DNAArtificial
SequenceSynthetic 698cagcagtatg gtagctcacc tcggacg
276999PRTArtificial SequenceSynthetic 699Gln Gln Tyr Gly
Ser Ser Pro Arg Thr1 5700363DNAArtificial SequenceSynthetic
700gaggtgcagc tggtgcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc
60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct
120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtaa taaatactat
180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa catgctgtat
240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc ggcttacgat
300attttgattg gttattcccc ggttgactac tggggccagg gaaccctggt caccgtctcc
360tca
363701121PRTArtificial SequenceSynthetic 701Glu Val Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10
15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
Ser Tyr20 25 30Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val35 40
45Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val50
55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Met Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys85 90 95Ala Ala Tyr Asp Ile Leu
Ile Gly Tyr Ser Pro Val Asp Tyr Trp Gly100 105
110Gln Gly Thr Leu Val Thr Val Ser Ser115
12070224DNAArtificial SequenceSynthetic 702ggattcacct tcagtagcta tggc
247038PRTArtificial
SequenceSynthetic 703Gly Phe Thr Phe Ser Ser Tyr Gly1
570424DNAArtificial SequenceSynthetic 704atatggtatg atggaagtaa taaa
247058PRTArtificial
SequenceSynthetic 705Ile Trp Tyr Asp Gly Ser Asn Lys1
570642DNAArtificial SequenceSynthetic 706gcggcttacg atattttgat tggttattcc
ccggttgact ac 4270714PRTArtificial
SequenceSynthetic 707Ala Ala Tyr Asp Ile Leu Ile Gly Tyr Ser Pro Val Asp
Tyr1 5 10708318DNAArtificial
SequenceSynthetic 708gatattgtga tgacccagtc tccagccacc ctgtctgtgt
ctccagggga aagagccacc 60ctctcctgca gggccagtca gactgttagt agcaacttag
cctggttcca gcagaaacct 120ggccaggctc ccagactcct catctatgat gcatccacca
gggccactgg tatcccagcc 180aggttcagtg gcagtgggtc tgggacagaa ttcactctca
ccatcagcag cctgcagtct 240gaagattttg cagtttatta ctgtcagcag tataataact
ggtacacttt tggccagggg 300accaagctgg agatcaaa
318709106PRTArtificial SequenceSynthetic 709Asp
Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1
5 10 15Glu Arg Ala Thr Leu Ser Cys Arg
Ala Ser Gln Thr Val Ser Ser Asn20 25
30Leu Ala Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile35
40 45Tyr Asp Ala Ser Thr Arg Ala Thr Gly Ile
Pro Ala Arg Phe Ser Gly50 55 60Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65
70 75 80Glu Asp Phe Ala Val Tyr Tyr
Cys Gln Gln Tyr Asn Asn Trp Tyr Thr85 90
95Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys100
10571018DNAArtificial SequenceSynthetic 710cagactgtta gtagcaac
187116PRTArtificial
SequenceSynthetic 711Gln Thr Val Ser Ser Asn1
57129DNAArtificial SequenceSynthetic 712gatgcatcc
97133PRTArtificial SequenceSynthetic
713Asp Ala Ser171424DNAArtificial SequenceSynthetic 714cagcagtata
ataactggta cact
247158PRTArtificial SequenceSynthetic 715Gln Gln Tyr Asn Asn Trp Tyr Thr1
5716357DNAArtificial SequenceSynthetic 716gaggtgcagc
tggtgcagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg
tctctggtgg ctccattacc agtggtggtt actactggac ctggatccgc 120cagcacccag
ggaagggcct ggaatggatt ggatacatca aatttagtgg gaacacctac 180tacaacccgt
ccctcaggag tcgagtcacc atatcacttg acacgtctaa gaatcagttc 240tccctgaata
tgacctctgt gactgccgcg gacacggccg tgtattattg tgcgagagca 300cctggaagtc
ataactttga catctggggc caagggacaa tggtcaccgt ctcttca
357717119PRTArtificial SequenceSynthetic 717Glu Val Gln Leu Val Gln Ser
Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10
15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Thr
Ser Gly20 25 30Gly Tyr Tyr Trp Thr Trp
Ile Arg Gln His Pro Gly Lys Gly Leu Glu35 40
45Trp Ile Gly Tyr Ile Lys Phe Ser Gly Asn Thr Tyr Tyr Asn Pro Ser50
55 60Leu Arg Ser Arg Val Thr Ile Ser Leu
Asp Thr Ser Lys Asn Gln Phe65 70 75
80Ser Leu Asn Met Thr Ser Val Thr Ala Ala Asp Thr Ala Val
Tyr Tyr85 90 95Cys Ala Arg Ala Pro Gly
Ser His Asn Phe Asp Ile Trp Gly Gln Gly100 105
110Thr Met Val Thr Val Ser Ser11571830DNAArtificial
SequenceSynthetic 718ggtggctcca ttaccagtgg tggttactac
3071910PRTArtificial SequenceSynthetic 719Gly Gly Ser
Ile Thr Ser Gly Gly Tyr Tyr1 5
1072021DNAArtificial SequenceSynthetic 720atcaaattta gtgggaacac c
217217PRTArtificial
SequenceSynthetic 721Ile Lys Phe Ser Gly Asn Thr1
572233DNAArtificial SequenceSynthetic 722gcgagagcac ctggaagtca taactttgac
atc 3372311PRTArtificial
SequenceSynthetic 723Ala Arg Ala Pro Gly Ser His Asn Phe Asp Ile1
5 10724324DNAArtificial SequenceSynthetic
724gccatccggt tgacccagtc tccagacacc ctgtctttgt ctccagggga aagagccacc
60ctctcctgca gggccagtgt gagtattagt aataactatt tagcctggta ccagcagaaa
120cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca
180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag aagactggag
240tctgcagatt ttgcaccgta ttactgtcag caatatagta ggtcaccgat caccttcggc
300caagggacac gactggagat taaa
324725108PRTArtificial SequenceSynthetic 725Ala Ile Arg Leu Thr Gln Ser
Pro Asp Thr Leu Ser Leu Ser Pro Gly1 5 10
15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Val Ser Ile Ser
Asn Asn20 25 30Tyr Leu Ala Trp Tyr Gln
Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu35 40
45Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser50
55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr
Leu Thr Ile Arg Arg Leu Glu65 70 75
80Ser Ala Asp Phe Ala Pro Tyr Tyr Cys Gln Gln Tyr Ser Arg
Ser Pro85 90 95Ile Thr Phe Gly Gln Gly
Thr Arg Leu Glu Ile Lys100 10572621DNAArtificial
SequenceSynthetic 726gtgagtatta gtaataacta t
217277PRTArtificial SequenceSynthetic 727Val Ser Ile Ser
Asn Asn Tyr1 57289DNAArtificial SequenceSynthetic
728ggtgcatcc
97293PRTArtificial SequenceSynthetic 729Gly Ala Ser173027DNAArtificial
SequenceSynthetic 730cagcaatata gtaggtcacc gatcacc
277319PRTArtificial SequenceSynthetic 731Gln Gln Tyr Ser
Arg Ser Pro Ile Thr1 5732357DNAArtificial SequenceSynthetic
732caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc
60acctgcactg tctctggtgg ctccatcaac agtgttactt actactggac ctggatccgc
120cagcacccag ggaggggcct agagtggatt gggtacatca aattcagtgg gagcacctac
180tacaacccgt ccctcaaggg tcgagtcacc atatcagtgg acacgtctaa gaaccaattc
240tcccttaaaa ttaactctgt gactgccgcg gacacggccg tgttttactg tgcgagagct
300tctggaagtc atacttttga tatctggggc caagggacaa tggtcaccgt ctcctca
357733119PRTArtificial SequenceSynthetic 733Gln Val Gln Leu Gln Glu Ser
Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10
15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Asn
Ser Val20 25 30Thr Tyr Tyr Trp Thr Trp
Ile Arg Gln His Pro Gly Arg Gly Leu Glu35 40
45Trp Ile Gly Tyr Ile Lys Phe Ser Gly Ser Thr Tyr Tyr Asn Pro Ser50
55 60Leu Lys Gly Arg Val Thr Ile Ser Val
Asp Thr Ser Lys Asn Gln Phe65 70 75
80Ser Leu Lys Ile Asn Ser Val Thr Ala Ala Asp Thr Ala Val
Phe Tyr85 90 95Cys Ala Arg Ala Ser Gly
Ser His Thr Phe Asp Ile Trp Gly Gln Gly100 105
110Thr Met Val Thr Val Ser Ser11573430DNAArtificial
SequenceSynthetic 734ggtggctcca tcaacagtgt tacttactac
3073510PRTArtificial SequenceSynthetic 735Gly Gly Ser
Ile Asn Ser Val Thr Tyr Tyr1 5
1073621DNAArtificial SequenceSynthetic 736atcaaattca gtgggagcac c
217377PRTArtificial
SequenceSynthetic 737Ile Lys Phe Ser Gly Ser Thr1
573833DNAArtificial SequenceSynthetic 738gcgagagctt ctggaagtca tacttttgat
atc 3373911PRTArtificial
SequenceSynthetic 739Ala Arg Ala Ser Gly Ser His Thr Phe Asp Ile1
5 10740324DNAArtificial SequenceSynthetic
740gaaacgacac tcacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc
60ctctcctgca gggccagtca gagtgttagc aacagctact tagcctggta ccagcagaaa
120cctggccagg ctcccaggct cctcatctct ggtgcgtcca gcagggtcac tggcatccca
180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag
240cctgaagatt ttggaatgta ttactgtcag cagtatagta ggtcaccgat caccttcggc
300caagggacca agctggagat caaa
324741108PRTArtificial SequenceSynthetic 741Glu Thr Thr Leu Thr Gln Ser
Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10
15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser
Asn Ser20 25 30Tyr Leu Ala Trp Tyr Gln
Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu35 40
45Ile Ser Gly Ala Ser Ser Arg Val Thr Gly Ile Pro Asp Arg Phe Ser50
55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr
Leu Thr Ile Ser Arg Leu Glu65 70 75
80Pro Glu Asp Phe Gly Met Tyr Tyr Cys Gln Gln Tyr Ser Arg
Ser Pro85 90 95Ile Thr Phe Gly Gln Gly
Thr Lys Leu Glu Ile Lys100 10574221DNAArtificial
SequenceSynthetic 742cagagtgtta gcaacagcta c
217437PRTArtificial SequenceSynthetic 743Gln Ser Val Ser
Asn Ser Tyr1 57449DNAArtificial SequenceSynthetic
744ggtgcgtcc
97453PRTArtificial SequenceSynthetic 745Gly Ala Ser174627DNAArtificial
SequenceSynthetic 746cagcagtata gtaggtcacc gatcacc
277479PRTArtificial SequenceSynthetic 747Gln Gln Tyr Ser
Arg Ser Pro Ile Thr1 5748357DNAArtificial SequenceSynthetic
748gaggtgcagc tggtgcagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc
60tcctgtgcag cctctggagt caccttggat gattatgcca tgcactgggt ccggcaagct
120ccagggaagg gcctggagtg ggtctcaagt attagttgga atagtggtag tataggctat
180gcggactctg tgaagggccg cttcaccatc tccagagaca acgccaagaa ctccctgtat
240ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaagatggg
300tggaacccgt actactttga ctattggggc cagggaataa cggtcaccgt ctcctca
357749119PRTArtificial SequenceSynthetic 749Glu Val Gln Leu Val Gln Ser
Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10
15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Val Thr Leu Asp
Asp Tyr20 25 30Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val35 40
45Ser Ser Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val50
55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ala Lys Asn Ser Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr
Tyr Cys85 90 95Ala Lys Asp Gly Trp Asn
Pro Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly100 105
110Ile Thr Val Thr Val Ser Ser11575024DNAArtificial
SequenceSynthetic 750ggagtcacct tggatgatta tgcc
247518PRTArtificial SequenceSynthetic 751Gly Val Thr Leu
Asp Asp Tyr Ala1 575224DNAArtificial SequenceSynthetic
752attagttgga atagtggtag tata
247538PRTArtificial SequenceSynthetic 753Ile Ser Trp Asn Ser Gly Ser Ile1
575436DNAArtificial SequenceSynthetic 754gcaaaagatg
ggtggaaccc gtactacttt gactat
3675512PRTArtificial SequenceSynthetic 755Ala Lys Asp Gly Trp Asn Pro Tyr
Tyr Phe Asp Tyr1 5 10756321DNAArtificial
SequenceSynthetic 756gacatccagt tgacccagtc tccatcctcc ctgtctgcat
ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcattaga agtgatttag
gctggtatca gcagaaacca 120gggaaagccc ctaagcgcct gatctatgct gcatccagtt
tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagaa ttcactctca
caatcagcag cctgcagcct 240gaagattttg caacttatta ctgtctacag cataatagtt
accctctcac tttcggcgga 300gggaccaagg tggaaatcaa a
321757107PRTArtificial SequenceSynthetic 757Asp
Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1
5 10 15Asp Arg Val Thr Ile Thr Cys Arg
Ala Ser Gln Gly Ile Arg Ser Asp20 25
30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile35
40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val
Pro Ser Arg Phe Ser Gly50 55 60Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65
70 75 80Glu Asp Phe Ala Thr Tyr Tyr
Cys Leu Gln His Asn Ser Tyr Pro Leu85 90
95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys100
10575818DNAArtificial SequenceSynthetic 758cagggcatta gaagtgat
187596PRTArtificial
SequenceSynthetic 759Gln Gly Ile Arg Ser Asp1
57609DNAArtificial SequenceSynthetic 760gctgcatcc
97613PRTArtificial SequenceSynthetic
761Ala Ala Ser176227DNAArtificial SequenceSynthetic 762ctacagcata
atagttaccc tctcact
277639PRTArtificial SequenceSynthetic 763Leu Gln His Asn Ser Tyr Pro Leu
Thr1 5764357DNAArtificial SequenceSynthetic 764cagatcacct
tgaaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcgccg
tctctggtga ctccttcagc agtggtaatt actactggag ctggatccgc 120caacacccag
ggaagggcct ggagtggatt gggtacatca agtacactgg gagcacctac 180tacaacccgt
ccctcaagag tcgagttatt atattagtag acacgtctaa gacccagttc 240tccctgaagc
tgagctctgt gaatgccgcg gacacggccg tgtattactg tgcgagagca 300cctggaactc
atgcttttga tgtttggggc caagggacaa tggtcaccgt ctcctca
357765119PRTArtificial SequenceSynthetic 765Gln Ile Thr Leu Lys Glu Ser
Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10
15Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Asp Ser Phe Ser
Ser Gly20 25 30Asn Tyr Tyr Trp Ser Trp
Ile Arg Gln His Pro Gly Lys Gly Leu Glu35 40
45Trp Ile Gly Tyr Ile Lys Tyr Thr Gly Ser Thr Tyr Tyr Asn Pro Ser50
55 60Leu Lys Ser Arg Val Ile Ile Leu Val
Asp Thr Ser Lys Thr Gln Phe65 70 75
80Ser Leu Lys Leu Ser Ser Val Asn Ala Ala Asp Thr Ala Val
Tyr Tyr85 90 95Cys Ala Arg Ala Pro Gly
Thr His Ala Phe Asp Val Trp Gly Gln Gly100 105
110Thr Met Val Thr Val Ser Ser11576630DNAArtificial
SequenceSynthetic 766ggtgactcct tcagcagtgg taattactac
3076710PRTArtificial SequenceSynthetic 767Gly Asp Ser
Phe Ser Ser Gly Asn Tyr Tyr1 5
1076821DNAArtificial SequenceSynthetic 768atcaagtaca ctgggagcac c
217697PRTArtificial
SequenceSynthetic 769Ile Lys Tyr Thr Gly Ser Thr1
577033DNAArtificial SequenceSynthetic 770gcgagagcac ctggaactca tgcttttgat
gtt 3377111PRTArtificial
SequenceSynthetic 771Ala Arg Ala Pro Gly Thr His Ala Phe Asp Val1
5 10772324DNAArtificial SequenceSynthetic
772gaaacgacac tcacgcagtc tccaggcacc ctgtctttgt ttccagggga aagagccacc
60ctctcctgca gggccagtca gagtgttagc agtagctact tagcctggta ccagcagaaa
120cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca
180gacaggttca gtggcagtgg gtctgtgaca gactccactc tcaccatcag cagcctggag
240cctgaagatt ttgcagtgta ttactgtcag cagtatagta ggtcaccgat caccttcggc
300caagggacca agctggagat caaa
324773108PRTArtificial SequenceSynthetic 773Glu Thr Thr Leu Thr Gln Ser
Pro Gly Thr Leu Ser Leu Phe Pro Gly1 5 10
15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser
Ser Ser20 25 30Tyr Leu Ala Trp Tyr Gln
Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu35 40
45Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser50
55 60Gly Ser Gly Ser Val Thr Asp Ser Thr
Leu Thr Ile Ser Ser Leu Glu65 70 75
80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Arg
Ser Pro85 90 95Ile Thr Phe Gly Gln Gly
Thr Lys Leu Glu Ile Lys100 10577421DNAArtificial
SequenceSynthetic 774cagagtgtta gcagtagcta c
217757PRTArtificial SequenceSynthetic 775Gln Ser Val Ser
Ser Ser Tyr1 57769DNAArtificial SequenceSynthetic
776ggtgcatcc
97773PRTArtificial SequenceSynthetic 777Gly Ala Ser177827DNAArtificial
SequenceSynthetic 778cagcagtata gtaggtcacc gatcacc
277799PRTArtificial SequenceSynthetic 779Gln Gln Tyr Ser
Arg Ser Pro Ile Thr1 5780360DNAArtificial SequenceSynthetic
780gaagtgcagc tggtgcagtc tgggggagcc ttggtacaac ctggggggtc cctgagactc
60tcctgtgcag cctctggatt cacctttaac aactttgcca tgacctgggt ccgccaggct
120ccagggaagg gcctggagtg ggtctcaact attagtggta gtggcgttga cacatactgc
180gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacactgtat
240ctgcaaatga acagcctgag agccgaggac acggccgtat attactgttc gaaagatggc
300gccttctata gtggctacga acactactgg ggccagggaa ccacggtcac cgtctcctca
360781120PRTArtificial SequenceSynthetic 781Glu Val Gln Leu Val Gln Ser
Gly Gly Ala Leu Val Gln Pro Gly Gly1 5 10
15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn
Asn Phe20 25 30Ala Met Thr Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val35 40
45Ser Thr Ile Ser Gly Ser Gly Val Asp Thr Tyr Cys Ala Asp Ser Val50
55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys85 90 95Ser Lys Asp Gly Ala Phe
Tyr Ser Gly Tyr Glu His Tyr Trp Gly Gln100 105
110Gly Thr Thr Val Thr Val Ser Ser115
12078224DNAArtificial SequenceSynthetic 782ggattcacct ttaacaactt tgcc
247838PRTArtificial
SequenceSynthetic 783Gly Phe Thr Phe Asn Asn Phe Ala1
578424DNAArtificial SequenceSynthetic 784attagtggta gtggcgttga caca
247858PRTArtificial
SequenceSynthetic 785Ile Ser Gly Ser Gly Val Asp Thr1
578639DNAArtificial SequenceSynthetic 786tcgaaagatg gcgccttcta tagtggctac
gaacactac 3978713PRTArtificial
SequenceSynthetic 787Ser Lys Asp Gly Ala Phe Tyr Ser Gly Tyr Glu His Tyr1
5 10788324DNAArtificial SequenceSynthetic
788gaaacgacac tcacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc
60ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa
120cctggccagg ctcccaggct cctcatctat ggtacatcca acagggccac tggcatccca
180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag
240tctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcacctcg gacgttcggc
300caagggacca aggtggagat caaa
324789108PRTArtificial SequenceSynthetic 789Glu Thr Thr Leu Thr Gln Ser
Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10
15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser
Ser Ser20 25 30Tyr Leu Ala Trp Tyr Gln
Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu35 40
45Ile Tyr Gly Thr Ser Asn Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser50
55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr
Leu Thr Ile Ser Arg Leu Glu65 70 75
80Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser
Ser Pro85 90 95Arg Thr Phe Gly Gln Gly
Thr Lys Val Glu Ile Lys100 10579021DNAArtificial
SequenceSynthetic 790cagagtgtta gcagcagcta c
217917PRTArtificial SequenceSynthetic 791Gln Ser Val Ser
Ser Ser Tyr1 57929DNAArtificial SequenceSynthetic
792ggtacatcc
97933PRTArtificial SequenceSynthetic 793Gly Thr Ser179427DNAArtificial
SequenceSynthetic 794cagcagtatg gtagctcacc tcggacg
277959PRTArtificial SequenceSynthetic 795Gln Gln Tyr Gly
Ser Ser Pro Arg Thr1 5796357DNAArtificial SequenceSynthetic
796gaagtgcagc tggtgcagtc tggacctgag gtgaagaagc ctggggcctc agtgaaggtc
60tcctgcaagg cttctggtta cacctttacc tactatggta tcagttggat acgacagacc
120cctggacaag ggcttgagtg gatgggatgg atcagcgctt acgatggtaa cacagactat
180gcacagaagt tccaagacag aatcaccatg accacagaca catcctcgac cacagcctac
240atggaactga ggagcctgag atctgacgac acggccgtct attactgtgc gaggtatagt
300tggaacaagc actggttcga cccctggggc cagggaacca tggtcaccgt ctcttca
357797119PRTArtificial SequenceSynthetic 797Glu Val Gln Leu Val Gln Ser
Gly Pro Glu Val Lys Lys Pro Gly Ala1 5 10
15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
Tyr Tyr20 25 30Gly Ile Ser Trp Ile Arg
Gln Thr Pro Gly Gln Gly Leu Glu Trp Met35 40
45Gly Trp Ile Ser Ala Tyr Asp Gly Asn Thr Asp Tyr Ala Gln Lys Phe50
55 60Gln Asp Arg Ile Thr Met Thr Thr Asp
Thr Ser Ser Thr Thr Ala Tyr65 70 75
80Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr
Tyr Cys85 90 95Ala Arg Tyr Ser Trp Asn
Lys His Trp Phe Asp Pro Trp Gly Gln Gly100 105
110Thr Met Val Thr Val Ser Ser11579824DNAArtificial
SequenceSynthetic 798ggttacacct ttacctacta tggt
247998PRTArtificial SequenceSynthetic 799Gly Tyr Thr Phe
Thr Tyr Tyr Gly1 580024DNAArtificial SequenceSynthetic
800atcagcgctt acgatggtaa caca
248018PRTArtificial SequenceSynthetic 801Ile Ser Ala Tyr Asp Gly Asn Thr1
580236DNAArtificial SequenceSynthetic 802gcgaggtata
gttggaacaa gcactggttc gacccc
3680312PRTArtificial SequenceSynthetic 803Ala Arg Tyr Ser Trp Asn Lys His
Trp Phe Asp Pro1 5 10804324DNAArtificial
SequenceSynthetic 804gaaattgtga tgacacagtc tccaggcacc ctgtctttgt
ctccagggga cagagccacc 60ctctcctgca gggccagtca gagtgttacc ggcagctact
tagcctggta ccagcagaaa 120cctggccagg ctcccagact cctcatctat ggtgcatcca
acagggccac tggcatccca 180gacaggttca ctggcagtgg gtctgggaca gacttcactc
tcaccatcag cagactggag 240cctgaagatt ttgcagtgta tttctgtcaa cagtctgctt
tctcaccgtg gacgttcggc 300caggggacca aggtggaaat caaa
324805108PRTArtificial SequenceSynthetic 805Glu
Ile Val Met Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1
5 10 15Asp Arg Ala Thr Leu Ser Cys Arg
Ala Ser Gln Ser Val Thr Gly Ser20 25
30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu35
40 45Ile Tyr Gly Ala Ser Asn Arg Ala Thr Gly
Ile Pro Asp Arg Phe Thr50 55 60Gly Ser
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65
70 75 80Pro Glu Asp Phe Ala Val Tyr
Phe Cys Gln Gln Ser Ala Phe Ser Pro85 90
95Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys100
10580621DNAArtificial SequenceSynthetic 806cagagtgtta ccggcagcta c
218077PRTArtificial
SequenceSynthetic 807Gln Ser Val Thr Gly Ser Tyr1
58089DNAArtificial SequenceSynthetic 808ggtgcatcc
98093PRTArtificial SequenceSynthetic
809Gly Ala Ser181027DNAArtificial SequenceSynthetic 810caacagtctg
ctttctcacc gtggacg
278119PRTArtificial SequenceSynthetic 811Gln Gln Ser Ala Phe Ser Pro Trp
Thr1 5812357DNAArtificial SequenceSynthetic 812gaggtgcagc
tggtgcagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60tcctgtgcag
cctctggagt caccttggat gattatgcca tgcactgggt ccggcaagct 120ccagggaagg
gcctggagtg ggtctcaagt attagttgga atagtggtag tataggctat 180gcggactctg
tgaagggccg cttcaccatc tccagagaca acgccaagaa ctccctgtat 240ctgcaaatga
acagtctgag agctgaggac acggccttgt attactgtgc aaaagatggg 300tggaacccgt
actactttga ctattggggc cagggaatac cggtcaccgt ctcctca
357813119PRTArtificial SequenceSynthetic 813Glu Val Gln Leu Val Gln Ser
Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10
15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Val Thr Leu Asp
Asp Tyr20 25 30Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val35 40
45Ser Ser Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val50
55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ala Lys Asn Ser Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr
Tyr Cys85 90 95Ala Lys Asp Gly Trp Asn
Pro Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly100 105
110Ile Pro Val Thr Val Ser Ser11581424DNAArtificial
SequenceSynthetic 814ggagtcacct tggatgatta tgcc
248158PRTArtificial SequenceSynthetic 815Gly Val Thr Leu
Asp Asp Tyr Ala1 581624DNAArtificial SequenceSynthetic
816attagttgga atagtggtag tata
248178PRTArtificial SequenceSynthetic 817Ile Ser Trp Asn Ser Gly Ser Ile1
581836DNAArtificial SequenceSynthetic 818gcaaaagatg
ggtggaaccc gtactacttt gactat
3681912PRTArtificial SequenceSynthetic 819Ala Lys Asp Gly Trp Asn Pro Tyr
Tyr Phe Asp Tyr1 5 10820321DNAArtificial
SequenceSynthetic 820gacatccaga tgacccagtc tccatcctcc ctgtctgcat
ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcattaga agtgatttag
gctggtatca gcagaaacca 120gggaaagccc ctaagcgcct gatctatgct gcatccagtt
tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagaa ttcactctca
caatcagcag cctgcagcct 240gaagattttg caacctatta ctgtctacag cataatagtt
accctctcac tttcggcgga 300gggaccaagc tggagatcaa a
321821107PRTArtificial SequenceSynthetic 821Asp
Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1
5 10 15Asp Arg Val Thr Ile Thr Cys Arg
Ala Ser Gln Gly Ile Arg Ser Asp20 25
30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile35
40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val
Pro Ser Arg Phe Ser Gly50 55 60Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65
70 75 80Glu Asp Phe Ala Thr Tyr Tyr
Cys Leu Gln His Asn Ser Tyr Pro Leu85 90
95Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys100
10582218DNAArtificial SequenceSynthetic 822cagggcatta gaagtgat
188236PRTArtificial
SequenceSynthetic 823Gln Gly Ile Arg Ser Asp1
58249DNAArtificial SequenceSynthetic 824gctgcatcc
98253PRTArtificial SequenceSynthetic
825Ala Ala Ser182627DNAArtificial SequenceSynthetic 826ctacagcata
atagttaccc tctcact
278279PRTArtificial SequenceSynthetic 827Leu Gln His Asn Ser Tyr Pro Leu
Thr1 5828357DNAArtificial SequenceSynthetic 828caggtacagc
tgcagcagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcgctg
tctctggtga ctccttcagc agtggtaatt actactggag ctggatccgc 120caacacccag
ggaagggcct ggagtggatt gggtacatca agtacactgg gagcacctac 180tacaacccgt
ccctcaagag tcgagttacc atattagtag acacgtctaa gacccagttc 240tccctgaagc
tgagctctgt gactgccgcg gacacggccg tgtattactg tgcgagagca 300cctggaactc
atgtttttga tgtctggggc caagggacaa tggtcaccgt ctcttca
357829119PRTArtificial SequenceSynthetic 829Gln Val Gln Leu Gln Gln Ser
Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10
15Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Asp Ser Phe Ser
Ser Gly20 25 30Asn Tyr Tyr Trp Ser Trp
Ile Arg Gln His Pro Gly Lys Gly Leu Glu35 40
45Trp Ile Gly Tyr Ile Lys Tyr Thr Gly Ser Thr Tyr Tyr Asn Pro Ser50
55 60Leu Lys Ser Arg Val Thr Ile Leu Val
Asp Thr Ser Lys Thr Gln Phe65 70 75
80Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val
Tyr Tyr85 90 95Cys Ala Arg Ala Pro Gly
Thr His Val Phe Asp Val Trp Gly Gln Gly100 105
110Thr Met Val Thr Val Ser Ser11583030DNAArtificial
SequenceSynthetic 830ggtgactcct tcagcagtgg taattactac
3083110PRTArtificial SequenceSynthetic 831Gly Asp Ser
Phe Ser Ser Gly Asn Tyr Tyr1 5
1083221DNAArtificial SequenceSynthetic 832atcaagtaca ctgggagcac c
218336PRTArtificial
SequenceSynthetic 833Lys Tyr Thr Gly Ser Thr1
583433DNAArtificial SequenceSynthetic 834gcgagagcac ctggaactca tgtttttgat
gtc 3383511PRTArtificial
SequenceSynthetic 835Ala Arg Ala Pro Gly Thr His Val Phe Asp Val1
5 10836324DNAArtificial SequenceSynthetic
836gacatccagt tgacccagtc tccaggcacc ctgtctttgc ttccagggga aagagccacc
60ctctcctgca gggccagtca gagtgttagc agtagctatt tagcctggta ccagcagaaa
120cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca
180gacaggttca gtggcagtgg gtctgtgaca gacttcactc tcaccatcag cagcctggag
240cctgaagatt ttgcagtgta ttactgtcag cagtatagta ggtcaccgat caccttcggc
300caagggacca aggtggagat caaa
324837108PRTArtificial SequenceSynthetic 837Asp Ile Gln Leu Thr Gln Ser
Pro Gly Thr Leu Ser Leu Leu Pro Gly1 5 10
15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser
Ser Ser20 25 30Tyr Leu Ala Trp Tyr Gln
Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu35 40
45Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser50
55 60Gly Ser Gly Ser Val Thr Asp Phe Thr
Leu Thr Ile Ser Ser Leu Glu65 70 75
80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Arg
Ser Pro85 90 95Ile Thr Phe Gly Gln Gly
Thr Lys Val Glu Ile Lys100 10583821DNAArtificial
SequenceSynthetic 838cagagtgtta gcagtagcta t
218397PRTArtificial SequenceSynthetic 839Gln Ser Val Ser
Ser Ser Tyr1 58409DNAArtificial SequenceSynthetic
840ggtgcatcc
98413PRTArtificial SequenceSynthetic 841Gly Ala Ser184227DNAArtificial
SequenceSynthetic 842cagcagtata gtaggtcacc gatcacc
278439PRTArtificial SequenceSynthetic 843Gln Gln Tyr Ser
Arg Ser Pro Ile Thr1 5844363DNAArtificial SequenceSynthetic
844caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc
60acctgcactg tctctggtgg ctccatcagc agtggtggtt actactggag ttggatccgc
120cagcacccag ggaagggcct ggagtggatt gggtacatcc attatagtgg gaacacccac
180tacaatccga ccctcaagag tcgaattacc atatcagtag acacgtctaa gaaccagttc
240tcccttgagg tgaactctgt gactgccgcg gacacggccg tatactactg tgcgaggaat
300atggttcggg gagttcactg gttcgacccc tggggccagg gaaccacggt caccgtctcc
360tca
363845121PRTArtificial SequenceSynthetic 845Gln Val Gln Leu Gln Glu Ser
Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10
15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser
Ser Gly20 25 30Gly Tyr Tyr Trp Ser Trp
Ile Arg Gln His Pro Gly Lys Gly Leu Glu35 40
45Trp Ile Gly Tyr Ile His Tyr Ser Gly Asn Thr His Tyr Asn Pro Thr50
55 60Leu Lys Ser Arg Ile Thr Ile Ser Val
Asp Thr Ser Lys Asn Gln Phe65 70 75
80Ser Leu Glu Val Asn Ser Val Thr Ala Ala Asp Thr Ala Val
Tyr Tyr85 90 95Cys Ala Arg Asn Met Val
Arg Gly Val His Trp Phe Asp Pro Trp Gly100 105
110Gln Gly Thr Thr Val Thr Val Ser Ser115
12084630DNAArtificial SequenceSynthetic 846ggtggctcca tcagcagtgg
tggttactac 3084710PRTArtificial
SequenceSynthetic 847Gly Gly Ser Ile Ser Ser Gly Gly Tyr Tyr1
5 1084821DNAArtificial SequenceSynthetic 848atccattata
gtgggaacac c
218497PRTArtificial SequenceSynthetic 849Ile His Tyr Ser Gly Asn Thr1
585039DNAArtificial SequenceSynthetic 850gcgaggaata tggttcgggg
agttcactgg ttcgacccc 3985113PRTArtificial
SequenceSynthetic 851Ala Arg Asn Met Val Arg Gly Val His Trp Phe Asp Pro1
5 10852324DNAArtificial SequenceSynthetic
852gaaatagtgt tgacacagtc tccaggcacc ctgtctttgt ctccagggga gagagccacc
60ctcttctgtt gggccagtcg gagtgttagc agcagctact tagcctggta ccagcagaaa
120cctggccagg ctcccaggct cctcatctct ggtgcatcca gcagggccac tggcatccca
180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag
240cctgaagatt ttgcagtata tttctgtcaa cagtatagta gttcaccgct cactttcggc
300ggagggacca agctggagat caaa
324853108PRTArtificial SequenceSynthetic 853Glu Ile Val Leu Thr Gln Ser
Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10
15Glu Arg Ala Thr Leu Phe Cys Trp Ala Ser Arg Ser Val Ser
Ser Ser20 25 30Tyr Leu Ala Trp Tyr Gln
Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu35 40
45Ile Ser Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser50
55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr
Leu Thr Ile Ser Arg Leu Glu65 70 75
80Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Tyr Ser Ser
Ser Pro85 90 95Leu Thr Phe Gly Gly Gly
Thr Lys Leu Glu Ile Lys100 10585421DNAArtificial
SequenceSynthetic 854cggagtgtta gcagcagcta c
218557PRTArtificial SequenceSynthetic 855Arg Ser Val Ser
Ser Ser Tyr1 58569DNAArtificial SequenceSynthetic
856ggtgcatcc
98573PRTArtificial SequenceSynthetic 857Gly Ala Ser185827DNAArtificial
SequenceSynthetic 858caacagtata gtagttcacc gctcact
278599PRTArtificial SequenceSynthetic 859Gln Gln Tyr Ser
Ser Ser Pro Leu Thr1 5860357DNAArtificial SequenceSynthetic
860caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc
60acctgcactg tctctagtga ctccatcagc agtggtaata actactggac ctggatccgc
120cagcacccag ggaggggcct ggagtggatt gggtacatca aatacactgg gagcgcccac
180tacaacccgt ccctcaagag tcgagtcacc atgtcagtag acacgtctaa gaatcagttc
240tccctgaaaa tgacctctgt gactgacgcg gacacggccg tgtattattg tgcgagggca
300cctggaagcc attcttttga tatatggggc cgagggacaa tggtcaccgt ctcctca
357861119PRTArtificial SequenceSynthetic 861Gln Val Gln Leu Gln Glu Ser
Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10
15Thr Leu Ser Leu Thr Cys Thr Val Ser Ser Asp Ser Ile Ser
Ser Gly20 25 30Asn Asn Tyr Trp Thr Trp
Ile Arg Gln His Pro Gly Arg Gly Leu Glu35 40
45Trp Ile Gly Tyr Ile Lys Tyr Thr Gly Ser Ala His Tyr Asn Pro Ser50
55 60Leu Lys Ser Arg Val Thr Met Ser Val
Asp Thr Ser Lys Asn Gln Phe65 70 75
80Ser Leu Lys Met Thr Ser Val Thr Asp Ala Asp Thr Ala Val
Tyr Tyr85 90 95Cys Ala Arg Ala Pro Gly
Ser His Ser Phe Asp Ile Trp Gly Arg Gly100 105
110Thr Met Val Thr Val Ser Ser11586230DNAArtificial
SequenceSynthetic 862agtgactcca tcagcagtgg taataactac
3086310PRTArtificial SequenceSynthetic 863Ser Asp Ser
Ile Ser Ser Gly Asn Asn Tyr1 5
1086421DNAArtificial SequenceSynthetic 864atcaaataca ctgggagcgc c
218657PRTArtificial
SequenceSynthetic 865Ile Lys Tyr Thr Gly Ser Ala1
586633DNAArtificial SequenceSynthetic 866gcgagggcac ctggaagcca ttcttttgat
ata 3386711PRTArtificial
SequenceSynthetic 867Ala Arg Ala Pro Gly Ser His Ser Phe Asp Ile1
5 10868324DNAArtificial SequenceSynthetic
868gatgttgtga tgacccagtc tccaggcacc ctgtttttgt ctccagggga aagagccacc
60ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa
120cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca
180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaacatcag cagactggag
240cctgaagatt ttgcactgta ttactgtcag cagtatagta ggtcaccgat caccttcggc
300caagggacac gactggagat taaa
324869108PRTArtificial SequenceSynthetic 869Asp Val Val Met Thr Gln Ser
Pro Gly Thr Leu Phe Leu Ser Pro Gly1 5 10
15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser
Ser Ser20 25 30Tyr Leu Ala Trp Tyr Gln
Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu35 40
45Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser50
55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr
Leu Asn Ile Ser Arg Leu Glu65 70 75
80Pro Glu Asp Phe Ala Leu Tyr Tyr Cys Gln Gln Tyr Ser Arg
Ser Pro85 90 95Ile Thr Phe Gly Gln Gly
Thr Arg Leu Glu Ile Lys100 10587021DNAArtificial
SequenceSynthetic 870cagagtgtta gcagcagcta c
218717PRTArtificial SequenceSynthetic 871Gln Ser Val Ser
Ser Ser Tyr1 58729DNAArtificial SequenceSynthetic
872ggtgcatcc
98733PRTArtificial SequenceSynthetic 873Gly Ala Ser187427DNAArtificial
SequenceSynthetic 874cagcagtata gtaggtcacc gatcacc
278759PRTArtificial SequenceSynthetic 875Gln Gln Tyr Ser
Arg Ser Pro Ile Thr1 5876360DNAArtificial SequenceSynthetic
876caggtgcagc tggtgcagtc tgggggaggc ttggtacaac ctggggggtc cctaagactc
60tcctgtgcag cctctggatt cacctctaac aactttgcca tgacctgggt ccgccaggct
120ccagggaagg gcctggagtg ggtctcaact attagtggta gtggcgttga cacatactgc
180gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacactgtat
240ctgcaaatga acagcctgag agtcgaggac acggccgtat attactgtgc taaagatggc
300gccttctata gtggctacga acactactgg ggccagggaa ccctggtcac cgtctcctca
360877120PRTArtificial SequenceSynthetic 877Gln Val Gln Leu Val Gln Ser
Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10
15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ser Asn
Asn Phe20 25 30Ala Met Thr Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val35 40
45Ser Thr Ile Ser Gly Ser Gly Val Asp Thr Tyr Cys Ala Asp Ser Val50
55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr
Tyr Cys85 90 95Ala Lys Asp Gly Ala Phe
Tyr Ser Gly Tyr Glu His Tyr Trp Gly Gln100 105
110Gly Thr Leu Val Thr Val Ser Ser115
12087824DNAArtificial SequenceSynthetic 878ggattcacct ctaacaactt tgcc
248798PRTArtificial
SequenceSynthetic 879Gly Phe Thr Ser Asn Asn Phe Ala1
588024DNAArtificial SequenceSynthetic 880attagtggta gtggcgttga caca
248818PRTArtificial
SequenceSynthetic 881Ile Ser Gly Ser Gly Val Asp Thr1
588239DNAArtificial SequenceSynthetic 882gctaaagatg gcgccttcta tagtggctac
gaacactac 3988313PRTArtificial
SequenceSynthetic 883Ala Lys Asp Gly Ala Phe Tyr Ser Gly Tyr Glu His Tyr1
5 10884324DNAArtificial SequenceSynthetic
884gatgttgtga tgacccagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc
60ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa
120cctggccagg ctcccaggct cctcatctat ggtacatcca acagggcctc tggcatccca
180gacaagttca ttggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag
240tctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcacctcg gacgttcggc
300caagggacca aagtggatat caaa
324885108PRTArtificial SequenceSynthetic 885Asp Val Val Met Thr Gln Ser
Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10
15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser
Ser Ser20 25 30Tyr Leu Ala Trp Tyr Gln
Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu35 40
45Ile Tyr Gly Thr Ser Asn Arg Ala Ser Gly Ile Pro Asp Lys Phe Ile50
55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr
Leu Thr Ile Ser Arg Leu Glu65 70 75
80Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser
Ser Pro85 90 95Arg Thr Phe Gly Gln Gly
Thr Lys Val Asp Ile Lys100 10588621DNAArtificial
SequenceSynthetic 886cagagtgtta gcagcagcta c
218877PRTArtificial SequenceSynthetic 887Gln Ser Val Ser
Ser Ser Tyr1 58889DNAArtificial SequenceSynthetic
888ggtacatcc
98893PRTArtificial SequenceSynthetic 889Gly Thr Ser189027DNAArtificial
SequenceSynthetic 890cagcagtatg gtagctcacc tcggacg
278919PRTArtificial SequenceSynthetic 891Gln Gln Tyr Gly
Ser Ser Pro Arg Thr1 5892360DNAArtificial SequenceSynthetic
892caggtgcagc tgcaggagtc cggccccggc ctggtgaagc cctcccagac cctgtccctg
60acctgcaccg tgtccggcgg ctccatcggc tccggcggct actactggtc ctggatccgg
120cagcaccccg gcaagggcct ggagtggatc ggctacgtgc actactccgg caacacctac
180tacaacccct ccctgaagtc ccgggtgacc atctccgtgg acacctccaa gaaccagttc
240tccctgaagc tgtcctccgt gaccgccgcc gacaccgccg tgtactactg cgcccgggcc
300ccccggggct accactactt cgcctactgg ggccagggca ccctggtgac cgtgtcctcc
360893120PRTArtificial SequenceSynthetic 893Gln Val Gln Leu Gln Glu Ser
Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10
15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Gly
Ser Gly20 25 30Gly Tyr Tyr Trp Ser Trp
Ile Arg Gln His Pro Gly Lys Gly Leu Glu35 40
45Trp Ile Gly Tyr Val His Tyr Ser Gly Asn Thr Tyr Tyr Asn Pro Ser50
55 60Leu Lys Ser Arg Val Thr Ile Ser Val
Asp Thr Ser Lys Asn Gln Phe65 70 75
80Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val
Tyr Tyr85 90 95Cys Ala Arg Ala Pro Arg
Gly Tyr His Tyr Phe Ala Tyr Trp Gly Gln100 105
110Gly Thr Leu Val Thr Val Ser Ser115
120894324DNAArtificial SequenceSynthetic 894gagatcgtgc tgacccagtc
ccccggcacc ctgtccctgt cccccggcga gcgggccacc 60ctgtcctgcc gggcctccca
gtccgtgtcc tcctcctacc tggcctggta ccagcagaag 120cccggccagg ccccccggct
gctgatctac ggcgcctcct cccgggccac cggcatcccc 180gaccggttct ccggctccgg
ctccggcacc gacttcaccc tgaccatctc ccggctggag 240cccgaggact tcgccgtgta
ctactgccag cagtacggct cctcccccct gaccttcggc 300ggcggcacca aggtggagat
caag 324895108PRTArtificial
SequenceSynthetic 895Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu
Ser Pro Gly1 5 10 15Glu
Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser20
25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
Ala Pro Arg Leu Leu35 40 45Ile Tyr Gly
Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser50 55
60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
Arg Leu Glu65 70 75
80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro85
90 95Leu Thr Phe Gly Gly Gly Thr Lys Val Glu
Ile Lys100 105896369DNAArtificial SequenceSynthetic
896caggtgcagc tggtggagtc cggcggcggc gtggtgcagc ccggccggtc cctgcggctg
60tcctgcgccg cctccggctt caccttctcc tcctacggca tgcactgggt gcggcaggcc
120cccggcaagg gcctggagtg ggtggccgtg ctgtggtacg acggcaccaa caagtactac
180gccgactccg tgaagggccg gttcaccatc tcccgggaca actccaagaa caccctgtac
240ctgcagatga actccctgcg ggccgaggac accgccgtgt actactgcgc ccgggaccac
300gacttccggt ccggctacga gggctggttc gacccctggg gccagggcac cctggtgacc
360gtgtcctcc
369897123PRTArtificial SequenceSynthetic 897Gln Val Gln Leu Val Glu Ser
Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10
15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
Ser Tyr20 25 30Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val35 40
45Ala Val Leu Trp Tyr Asp Gly Thr Asn Lys Tyr Tyr Ala Asp Ser Val50
55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys85 90 95Ala Arg Asp His Asp Phe
Arg Ser Gly Tyr Glu Gly Trp Phe Asp Pro100 105
110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser115
120898321DNAArtificial SequenceSynthetic 898gagatcgtgc tgacccagtc
ccccgccacc ctgtccctgt cccccggcga gcgggccacc 60ctgtcctgcc gggcctccca
gtccgtgtcc tcctacctgg cctggtacca gcagaagccc 120ggccaggccc cccggctgct
gatctacgac gcctccaacc gggccaccgg catccccgcc 180cggttctccg gctccggctc
cggcaccgac ttcaccctga ccatctcctc cctggagccc 240gaggacttcg ccgtgtacta
ctgccagcac cggtccaact ggccccccac cttcggcggc 300ggcaccaagg tggagatcaa g
321899107PRTArtificial
SequenceSynthetic 899Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu
Ser Pro Gly1 5 10 15Glu
Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr20
25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala
Pro Arg Leu Leu Ile35 40 45Tyr Asp Ala
Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly50 55
60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
Leu Glu Pro65 70 75
80Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Arg Ser Asn Trp Pro Pro85
90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
Lys100 105900369DNAArtificial SequenceSynthetic
900caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc
60tcctgtgcag cgtctggatt caccttcagt agttatggca tgcactgggt ccgccaggct
120ccaggcaagg ggctggagtg ggtgtcattt ttatggtatg atggaactaa taaaaactat
180gtagagtccg tgaagggccg attcaccatc tcaagagaca attccaagaa tatgctgtat
240ctggaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatcac
300gattttagga gtggttatga ggggtggttc gacccctggg gccagggaac cctggtcacc
360gtctcctca
369901123PRTArtificial SequenceSynthetic 901Gln Val Gln Leu Val Glu Ser
Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10
15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
Ser Tyr20 25 30Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val35 40
45Ser Phe Leu Trp Tyr Asp Gly Thr Asn Lys Asn Tyr Val Glu Ser Val50
55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Met Leu Tyr65 70 75
80Leu Glu Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys85 90 95Ala Arg Asp His Asp Phe
Arg Ser Gly Tyr Glu Gly Trp Phe Asp Pro100 105
110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser115
120902321DNAArtificial SequenceSynthetic 902gaaatagtgt tgacacagtc
tccagccacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca
gagtgttagc agctacttag cctggtacca acagaaacct 120ggccaggctc ccaggctcct
catctatgat gcatccaaca gggccactgg catcccagcc 180aggttcagtg gcagtgggtc
tgggacagac ttcactctca ccatcagcag cctagagcct 240gaagattttg cagtttatta
ctgtcaacac cgtagcaact ggcctcccac tttcggcgga 300gggaccaagg tggaaatcaa a
321903107PRTArtificial
SequenceSynthetic 903Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu
Ser Pro Gly1 5 10 15Glu
Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr20
25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala
Pro Arg Leu Leu Ile35 40 45Tyr Asp Ala
Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly50 55
60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
Leu Glu Pro65 70 75
80Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Arg Ser Asn Trp Pro Pro85
90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
Lys100 105904363DNAArtificial SequenceSynthetic
904caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc
60acctgcactg tctctggtgg ctccatcagc agtggtggtt actactggag ttggatccgc
120cagcacccag ggaagggcct ggagtggatt gggtacatcc attatagtgg gaacacccac
180tacaatccga ccctcaagag tcgaattacc atatcagtag acacgtctaa gaaccagttc
240tcccttgagg tgaactctgt gactgccgcg gacacggccg tatactactg tgcgaggaat
300atggttcggg gagttcactg gttcgacccc tggggccagg gaaccacggt caccgtctcc
360tca
363905121PRTArtificial SequenceSynthetic 905Gln Val Gln Leu Gln Glu Ser
Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10
15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser
Ser Gly20 25 30Gly Tyr Tyr Trp Ser Trp
Ile Arg Gln His Pro Gly Lys Gly Leu Glu35 40
45Trp Ile Gly Tyr Ile His Tyr Ser Gly Asn Thr His Tyr Asn Pro Thr50
55 60Leu Lys Ser Arg Ile Thr Ile Ser Val
Asp Thr Ser Lys Asn Gln Phe65 70 75
80Ser Leu Glu Val Asn Ser Val Thr Ala Ala Asp Thr Ala Val
Tyr Tyr85 90 95Cys Ala Arg Asn Met Val
Arg Gly Val His Trp Phe Asp Pro Trp Gly100 105
110Gln Gly Thr Thr Val Thr Val Ser Ser115
120906324DNAArtificial SequenceSynthetic 906gaaatagtgt tgacacagtc
tccaggcacc ctgtctttgt ctccagggga gagagccacc 60ctcttctgtt gggccagtcg
gagtgttagc agcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct
cctcatctct ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg
gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtata
tttctgtcaa cagtatagta gttcaccgct cactttcggc 300ggagggacca agctggagat
caaa 324907108PRTArtificial
SequenceSynthetic 907Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu
Ser Pro Gly1 5 10 15Glu
Arg Ala Thr Leu Phe Cys Trp Ala Ser Arg Ser Val Ser Ser Ser20
25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
Ala Pro Arg Leu Leu35 40 45Ile Ser Gly
Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser50 55
60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
Arg Leu Glu65 70 75
80Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Tyr Ser Ser Ser Pro85
90 95Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu
Ile Lys100 105908363DNAArtificial SequenceSynthetic
908caggtgcagc tgcaggagtc cggccccggc ctggtgaagc cctcccagac cctgtccctg
60acctgcaccg tgtccggcgg ctccatctcc tccggcggct actactggtc ctggatccgg
120cagcaccccg gcaagggcct ggagtggatc ggctacatcc actactccgg caacacctac
180tacaacccct ccctgaagtc ccgggtgacc atctccgtgg acacctccaa gaaccagttc
240tccctgaagc tgtcctccgt gaccgccgcc gacaccgccg tgtactactg cgcccggaac
300atggtgcggg gcgtgcactg gttcgacccc tggggccagg gcaccctggt gaccgtgtcc
360tcc
363909121PRTArtificial SequenceSynthetic 909Gln Val Gln Leu Gln Glu Ser
Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10
15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser
Ser Gly20 25 30Gly Tyr Tyr Trp Ser Trp
Ile Arg Gln His Pro Gly Lys Gly Leu Glu35 40
45Trp Ile Gly Tyr Ile His Tyr Ser Gly Asn Thr Tyr Tyr Asn Pro Ser50
55 60Leu Lys Ser Arg Val Thr Ile Ser Val
Asp Thr Ser Lys Asn Gln Phe65 70 75
80Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val
Tyr Tyr85 90 95Cys Ala Arg Asn Met Val
Arg Gly Val His Trp Phe Asp Pro Trp Gly100 105
110Gln Gly Thr Leu Val Thr Val Ser Ser115
120910324DNAArtificial SequenceSynthetic 910gagatcgtgc tgacccagtc
ccccggcacc ctgtccctgt cccccggcga gcgggccacc 60ctgtcctgcc gggcctcccg
gtccgtgtcc tcctcctacc tggcctggta ccagcagaag 120cccggccagg ccccccggct
gctgatctac ggcgcctcct cccgggccac cggcatcccc 180gaccggttct ccggctccgg
ctccggcacc gacttcaccc tgaccatctc ccggctggag 240cccgaggact tcgccgtgta
ctactgccag cagtactcct cctcccccct gaccttcggc 300ggcggcacca aggtggagat
caag 324911108PRTArtificial
SequenceSynthetic 911Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu
Ser Pro Gly1 5 10 15Glu
Arg Ala Thr Leu Ser Cys Arg Ala Ser Arg Ser Val Ser Ser Ser20
25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
Ala Pro Arg Leu Leu35 40 45Ile Tyr Gly
Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser50 55
60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
Arg Leu Glu65 70 75
80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Ser Ser Pro85
90 95Leu Thr Phe Gly Gly Gly Thr Lys Val Glu
Ile Lys100 105912363DNAArtificial SequenceSynthetic
912caggtgcagc tgcaggagtc gggcctagga ctggtgaagc cttcacagac cctgtccctc
60acctgcactg tctctggtgg ctccatcagc agtggtggtt actactggag ttggatccgc
120cagcacccag ggaagggcct ggagtggatt gggtacatcc attatagtgg gaacacccac
180tacaatccga ccctcaagag tcgaattacc atatcagtag acacgtctaa gaaccagttc
240tcccttgagg tgaactctgt gactgccgcg gacacggccg tatactactg tgcgaggaat
300atggttcggg gagttcactg gttcgacccc tggggccagg gaaccctggt caccgtctcc
360tca
363913121PRTArtificial SequenceSynthetic 913Gln Val Gln Leu Gln Glu Ser
Gly Leu Gly Leu Val Lys Pro Ser Gln1 5 10
15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser
Ser Gly20 25 30Gly Tyr Tyr Trp Ser Trp
Ile Arg Gln His Pro Gly Lys Gly Leu Glu35 40
45Trp Ile Gly Tyr Ile His Tyr Ser Gly Asn Thr His Tyr Asn Pro Thr50
55 60Leu Lys Ser Arg Ile Thr Ile Ser Val
Asp Thr Ser Lys Asn Gln Phe65 70 75
80Ser Leu Glu Val Asn Ser Val Thr Ala Ala Asp Thr Ala Val
Tyr Tyr85 90 95Cys Ala Arg Asn Met Val
Arg Gly Val His Trp Phe Asp Pro Trp Gly100 105
110Gln Gly Thr Leu Val Thr Val Ser Ser115
120914324DNAArtificial SequenceSynthetic 914gaaatagtgt tgacacagtc
tccaggcacc ctgtctttgt ctccagggga gagagccacc 60ctcttctgtt gggccagtcg
gagtgttagc agcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct
cctcatctct ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg
gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtata
tttctgtcaa cagtatagta gttcaccgct cactttcggc 300ggagggacca aggtggaaat
caaa 324915108PRTArtificial
SequenceSynthetic 915Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu
Ser Pro Gly1 5 10 15Glu
Arg Ala Thr Leu Phe Cys Trp Ala Ser Arg Ser Val Ser Ser Ser20
25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
Ala Pro Arg Leu Leu35 40 45Ile Ser Gly
Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser50 55
60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
Arg Leu Glu65 70 75
80Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Tyr Ser Ser Ser Pro85
90 95Leu Thr Phe Gly Gly Gly Thr Lys Val Glu
Ile Lys100 105916357DNAArtificial SequenceSynthetic
916caggtgcagc tgcaggagtc cggccccggc ctggtgaagc cctcccagac cctgtccctg
60acctgcaccg tgtccggcgg ctccatcacc tccggcggct actactggtc ctggatccgg
120cagcaccccg gcaagggcct ggagtggatc ggctacatca agttctccgg caacacctac
180tacaacccct ccctgaagtc ccgggtgacc atctccgtgg acacctccaa gaaccagttc
240tccctgaagc tgtcctccgt gaccgccgcc gacaccgccg tgtactactg cgcccgggcc
300cccggctccc acaacttcga catctggggc cagggcacca tggtgaccgt gtcctcc
357917119PRTArtificial SequenceSynthetic 917Gln Val Gln Leu Gln Glu Ser
Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10
15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Thr
Ser Gly20 25 30Gly Tyr Tyr Trp Ser Trp
Ile Arg Gln His Pro Gly Lys Gly Leu Glu35 40
45Trp Ile Gly Tyr Ile Lys Phe Ser Gly Asn Thr Tyr Tyr Asn Pro Ser50
55 60Leu Lys Ser Arg Val Thr Ile Ser Val
Asp Thr Ser Lys Asn Gln Phe65 70 75
80Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val
Tyr Tyr85 90 95Cys Ala Arg Ala Pro Gly
Ser His Asn Phe Asp Ile Trp Gly Gln Gly100 105
110Thr Met Val Thr Val Ser Ser115918324DNAArtificial
SequenceSynthetic 918gagatcgtgc tgacccagtc ccccggcacc ctgtccctgt
cccccggcga gcgggccacc 60ctgtcctgcc gggcctccgt gtccatctcc aacaactacc
tggcctggta ccagcagaag 120cccggccagg ccccccggct gctgatctac ggcgcctcct
cccgggccac cggcatcccc 180gaccggttct ccggctccgg ctccggcacc gacttcaccc
tgaccatccg gcggctggag 240cccgaggact tcgcccccta ctactgccag cagtactccc
ggtcccccat caccttcggc 300cagggcaccc ggctggagat caag
324919108PRTArtificial SequenceSynthetic 919Glu
Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1
5 10 15Glu Arg Ala Thr Leu Ser Cys Arg
Ala Ser Val Ser Ile Ser Asn Asn20 25
30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu35
40 45Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly
Ile Pro Asp Arg Phe Ser50 55 60Gly Ser
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Arg Arg Leu Glu65
70 75 80Pro Glu Asp Phe Ala Pro Tyr
Tyr Cys Gln Gln Tyr Ser Arg Ser Pro85 90
95Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys100
105920360DNAArtificial SequenceSynthetic 920gaggtgcagc tggtggagtc
cggcggcggc ctggtgcagc ccggcggctc cctgcggctg 60tcctgcgccg cctccggctt
caccttcaac aacttcgcca tgtcctgggt gcggcaggcc 120cccggcaagg gcctggagtg
ggtgtccgcc atctccggct ccggcgtgga cacctactac 180gccgactccg tgaagggccg
gttcaccatc tcccgggaca actccaagaa caccctgtac 240ctgcagatga actccctgcg
ggccgaggac accgccgtgt actactgctc caaggacggc 300gccttctact ccggctacga
gcactactgg ggccagggca ccctggtgac cgtgtcctcc 360921120PRTArtificial
SequenceSynthetic 921Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
Pro Gly Gly1 5 10 15Ser
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asn Phe20
25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys
Gly Leu Glu Trp Val35 40 45Ser Ala Ile
Ser Gly Ser Gly Val Asp Thr Tyr Tyr Ala Asp Ser Val50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys85
90 95Ser Lys Asp Gly Ala Phe Tyr Ser Gly Tyr
Glu His Tyr Trp Gly Gln100 105 110Gly Thr
Leu Val Thr Val Ser Ser115 120922324DNAArtificial
SequenceSynthetic 922gagatcgtgc tgacccagtc ccccggcacc ctgtccctgt
cccccggcga gcgggccacc 60ctgtcctgcc gggcctccca gtccgtgtcc tcctcctacc
tggcctggta ccagcagaag 120cccggccagg ccccccggct gctgatctac ggcacctcct
cccgggccac cggcatcccc 180gaccggttct ccggctccgg ctccggcacc gacttcaccc
tgaccatctc ccggctggag 240cccgaggact tcgccgtgta ctactgccag cagtacggct
cctccccccg gaccttcggc 300cagggcacca aggtggagat caag
324923108PRTArtificial SequenceSynthetic 923Glu
Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1
5 10 15Glu Arg Ala Thr Leu Ser Cys Arg
Ala Ser Gln Ser Val Ser Ser Ser20 25
30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu35
40 45Ile Tyr Gly Thr Ser Ser Arg Ala Thr Gly
Ile Pro Asp Arg Phe Ser50 55 60Gly Ser
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65
70 75 80Pro Glu Asp Phe Ala Val Tyr
Tyr Cys Gln Gln Tyr Gly Ser Ser Pro85 90
95Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys100
105924357DNAArtificial SequenceSynthetic 924caggtgcagc tggtgcagtc
cggcgccgag gtgaagaagc ccggcgcctc cgtgaaggtg 60tcctgcaagg cctccggcta
caccttcacc tactacggca tctcctgggt gcggcaggcc 120cccggccagg gcctggagtg
gatgggctgg atctccgcct acgacggcaa caccaactac 180gcccagaagc tgcagggccg
ggtgaccatg accaccgaca cctccacctc caccgcctac 240atggagctgc ggtccctgcg
gtccgacgac accgccgtgt actactgcgc ccggtactcc 300tggaacaagc actggttcga
cccctggggc cagggcaccc tggtgaccgt gtcctcc 357925119PRTArtificial
SequenceSynthetic 925Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
Pro Gly Ala1 5 10 15Ser
Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Tyr Tyr20
25 30Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln
Gly Leu Glu Trp Met35 40 45Gly Trp Ile
Ser Ala Tyr Asp Gly Asn Thr Asn Tyr Ala Gln Lys Leu50 55
60Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser
Thr Ala Tyr65 70 75
80Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys85
90 95Ala Arg Tyr Ser Trp Asn Lys His Trp Phe
Asp Pro Trp Gly Gln Gly100 105 110Thr Leu
Val Thr Val Ser Ser115926324DNAArtificial SequenceSynthetic 926gagatcgtgc
tgacccagtc ccccggcacc ctgtccctgt cccccggcga gcgggccacc 60ctgtcctgcc
gggcctccca gtccgtgacc ggctcctacc tggcctggta ccagcagaag 120cccggccagg
ccccccggct gctgatctac ggcgcctcct cccgggccac cggcatcccc 180gaccggttct
ccggctccgg ctccggcacc gacttcaccc tgaccatctc ccggctggag 240cccgaggact
tcgccgtgta ctactgccag cagtccgcct tctccccctg gaccttcggc 300cagggcacca
aggtggagat caag
324927108PRTArtificial SequenceSynthetic 927Glu Ile Val Leu Thr Gln Ser
Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10
15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr
Gly Ser20 25 30Tyr Leu Ala Trp Tyr Gln
Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu35 40
45Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser50
55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr
Leu Thr Ile Ser Arg Leu Glu65 70 75
80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Ala Phe
Ser Pro85 90 95Trp Thr Phe Gly Gln Gly
Thr Lys Val Glu Ile Lys100 1059288PRTArtificial
SequenceSynthetic 928Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa1
59298PRTArtificial SequenceSynthetic 929Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa1
593016PRTArtificial SequenceSynthetic 930Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa1 5
10 159317PRTArtificial SequenceSynthetic 931Xaa Xaa
Xaa Xaa Xaa Xaa Xaa1 59323PRTArtificial SequenceSynthetic
932Xaa Xaa Xaa19339PRTArtificial SequenceSynthetic 933Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa1 5934357DNAArtificial SequenceSynthetic
934caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc
60acctgcactg tctctggtgg ctccattacc agtggtggtt actactggac ctggatccgc
120cagcacccag ggaagggcct ggaatggatt ggatacatca aatttagtgg gaacacctac
180tacaacccgt ccctcaggag tcgagtcacc atatcacttg acacgtctaa gaatcagttc
240tccctgaata tgacctctgt gactgccgcg gacacggccg tgtattattg tgcgagagca
300cctggaagtc ataactttga catctggggc caagggacaa tggtcaccgt ctcttca
357935119PRTArtificial SequenceSynthetic 935Gln Val Gln Leu Gln Glu Ser
Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10
15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Thr
Ser Gly20 25 30Gly Tyr Tyr Trp Thr Trp
Ile Arg Gln His Pro Gly Lys Gly Leu Glu35 40
45Trp Ile Gly Tyr Ile Lys Phe Ser Gly Asn Thr Tyr Tyr Asn Pro Ser50
55 60Leu Arg Ser Arg Val Thr Ile Ser Leu
Asp Thr Ser Lys Asn Gln Phe65 70 75
80Ser Leu Asn Met Thr Ser Val Thr Ala Ala Asp Thr Ala Val
Tyr Tyr85 90 95Cys Ala Arg Ala Pro Gly
Ser His Asn Phe Asp Ile Trp Gly Gln Gly100 105
110Thr Met Val Thr Val Ser Ser115936324DNAArtificial
SequenceSynthetic 936gaaatcgtgt tgacccagtc tccagacacc ctgtctttgt
ctccagggga aagagccacc 60ctctcctgca gggccagtgt gagtattagt aataactatt
tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctat ggtgcatcca
gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc
tcaccatcag aagactggag 240tctgcagatt ttgcaccgta ttactgtcag caatatagta
ggtcaccgat caccttcggc 300caagggacac gactggagat taaa
324937108PRTArtificial SequenceSynthetic 937Glu
Ile Val Leu Thr Gln Ser Pro Asp Thr Leu Ser Leu Ser Pro Gly1
5 10 15Glu Arg Ala Thr Leu Ser Cys Arg
Ala Ser Val Ser Ile Ser Asn Asn20 25
30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu35
40 45Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly
Ile Pro Asp Arg Phe Ser50 55 60Gly Ser
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Arg Arg Leu Glu65
70 75 80Ser Ala Asp Phe Ala Pro Tyr
Tyr Cys Gln Gln Tyr Ser Arg Ser Pro85 90
95Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys100
105938360DNAArtificial SequenceSynthetic 938gaagtgcagc tggtggagtc
tgggggagcc ttggtacaac ctggggggtc cctgagactc 60tcctgtgcag cctctggatt
cacctttaac aactttgcca tgacctgggt ccgccaggct 120ccagggaagg gcctggagtg
ggtctcaact attagtggta gtggcgttga cacatactgc 180gcagactccg tgaagggccg
gttcaccatc tccagagaca attccaagaa cacactgtat 240ctgcaaatga acagcctgag
agccgaggac acggccgtat attactgttc gaaagatggc 300gccttctata gtggctacga
acactactgg ggccagggaa ccctggtcac cgtctcctca 360939120PRTArtificial
SequenceSynthetic 939Glu Val Gln Leu Val Glu Ser Gly Gly Ala Leu Val Gln
Pro Gly Gly1 5 10 15Ser
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asn Phe20
25 30Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys
Gly Leu Glu Trp Val35 40 45Ser Thr Ile
Ser Gly Ser Gly Val Asp Thr Tyr Cys Ala Asp Ser Val50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys85
90 95Ser Lys Asp Gly Ala Phe Tyr Ser Gly Tyr
Glu His Tyr Trp Gly Gln100 105 110Gly Thr
Leu Val Thr Val Ser Ser115 120940324DNAArtificial
SequenceSynthetic 940gaaattgtgc tcacgcagtc tccaggcacc ctgtctttgt
ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcagctact
tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctat ggtacatcca
acagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc
tcaccatcag cagactggag 240tctgaagatt ttgcagtgta ttactgtcag cagtatggta
gctcacctcg gacgttcggc 300caagggacca aggtggagat caaa
324941108PRTArtificial SequenceSynthetic 941Glu
Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1
5 10 15Glu Arg Ala Thr Leu Ser Cys Arg
Ala Ser Gln Ser Val Ser Ser Ser20 25
30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu35
40 45Ile Tyr Gly Thr Ser Asn Arg Ala Thr Gly
Ile Pro Asp Arg Phe Ser50 55 60Gly Ser
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65
70 75 80Ser Glu Asp Phe Ala Val Tyr
Tyr Cys Gln Gln Tyr Gly Ser Ser Pro85 90
95Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys100
105942357DNAArtificial SequenceSynthetic 942caggtgcagc tggtgcagtc
tggacctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggtta
cacctttacc tactatggta tcagttggat acgacagacc 120cctggacaag ggcttgagtg
gatgggatgg atcagcgctt acgatggtaa cacagactat 180gcacagaagt tccaagacag
aatcaccatg accacagaca catcctcgac cacagcctac 240atggaactga ggagcctgag
atctgacgac acggccgtct attactgtgc gaggtatagt 300tggaacaagc actggttcga
cccctggggc cagggaaccc tggtcaccgt ctcttca 357943119PRTArtificial
SequenceSynthetic 943Gln Val Gln Leu Val Gln Ser Gly Pro Glu Val Lys Lys
Pro Gly Ala1 5 10 15Ser
Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Tyr Tyr20
25 30Gly Ile Ser Trp Ile Arg Gln Thr Pro Gly Gln
Gly Leu Glu Trp Met35 40 45Gly Trp Ile
Ser Ala Tyr Asp Gly Asn Thr Asp Tyr Ala Gln Lys Phe50 55
60Gln Asp Arg Ile Thr Met Thr Thr Asp Thr Ser Ser Thr
Thr Ala Tyr65 70 75
80Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys85
90 95Ala Arg Tyr Ser Trp Asn Lys His Trp Phe
Asp Pro Trp Gly Gln Gly100 105 110Thr Leu
Val Thr Val Ser Ser115944324DNAArtificial SequenceSynthetic 944gaaattgtgt
tgacacagtc tccaggcacc ctgtctttgt ctccagggga cagagccacc 60ctctcctgca
gggccagtca gagtgttacc ggcagctact tagcctggta ccagcagaaa 120cctggccagg
ctcccagact cctcatctat ggtgcatcca acagggccac tggcatccca 180gacaggttca
ctggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt
ttgcagtgta tttctgtcaa cagtctgctt tctcaccgtg gacgttcggc 300caggggacca
aggtggaaat caaa
324945108PRTArtificial SequenceSynthetic 945Glu Ile Val Leu Thr Gln Ser
Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10
15Asp Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr
Gly Ser20 25 30Tyr Leu Ala Trp Tyr Gln
Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu35 40
45Ile Tyr Gly Ala Ser Asn Arg Ala Thr Gly Ile Pro Asp Arg Phe Thr50
55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr
Leu Thr Ile Ser Arg Leu Glu65 70 75
80Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Ser Ala Phe
Ser Pro85 90 95Trp Thr Phe Gly Gln Gly
Thr Lys Val Glu Ile Lys100 105946361DNAArtificial
SequenceSynthetic 946caggtgcagt tgcaggagtc gggcccagga ctggtgaagc
cttcacagac cctgtccctc 60acctgcactg tctctggtgg ctccatcggc agtggtggtt
actactggag ctggatccgc 120cagcacccag ggaagggcct ggagtggatt gggtacgtcc
attacagtgg gaacacccac 180tacaacccgt ccctcaagag tcgactttcc atatcaatag
acacgtctaa gatccagttc 240tccctgaagc tgagctctgt gactgccgcg gacacggccg
tgtattactg tgcgagagcc 300ccccgtggat accattactt tgcctactgg ggccagggaa
ccctggtcac cgtctcctca 360g
361947120PRTArtificial SequenceSynthetic 947Gln
Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1
5 10 15Thr Leu Ser Leu Thr Cys Thr Val
Ser Gly Gly Ser Ile Gly Ser Gly20 25
30Gly Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu35
40 45Trp Ile Gly Tyr Val His Tyr Ser Gly Asn
Thr His Tyr Asn Pro Ser50 55 60Leu Lys
Ser Arg Leu Ser Ile Ser Ile Asp Thr Ser Lys Ile Gln Phe65
70 75 80Ser Leu Lys Leu Ser Ser Val
Thr Ala Ala Asp Thr Ala Val Tyr Tyr85 90
95Cys Ala Arg Ala Pro Arg Gly Tyr His Tyr Phe Ala Tyr Trp Gly Gln100
105 110Gly Thr Leu Val Thr Val Ser Ser115
120948325DNAArtificial SequenceSynthetic 948gaaattgtgt
tgacacaatc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca
gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120cctggccagg
ctcccaggct cctcatcttt ggtgcatcca gcagggccac tggcatccca 180gacaggttca
gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt
ttgcagtgta ttactgtcag cagtatggta gctcaccgct cactttcggc 300ggagggacca
aggtggagat caaac
325949108PRTArtificial SequenceSynthetic 949Glu Ile Val Leu Thr Gln Ser
Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10
15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser
Ser Ser20 25 30Tyr Leu Ala Trp Tyr Gln
Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu35 40
45Ile Phe Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser50
55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr
Leu Thr Ile Ser Arg Leu Glu65 70 75
80Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser
Ser Pro85 90 95Leu Thr Phe Gly Gly Gly
Thr Lys Val Glu Ile Lys100 105950330PRTArtificial
SequenceSynthetic 950Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
Ser Ser Lys1 5 10 15Ser
Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr20
25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
Gly Ala Leu Thr Ser35 40 45Gly Val His
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser50 55
60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
Thr Gln Thr65 70 75
80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys85
90 95Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
His Thr Cys Pro Pro Cys100 105 110Pro Ala
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro115
120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
Glu Val Thr Cys130 135 140Val Val Val Asp
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150
155 160Tyr Val Asp Gly Val Glu Val His Asn
Ala Lys Thr Lys Pro Arg Glu165 170 175Glu
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu180
185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
Cys Lys Val Ser Asn195 200 205Lys Ala Leu
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly210
215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
Ser Arg Asp Glu225 230 235
240Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr245
250 255Pro Ser Asp Ile Ala Val Glu Trp Glu
Ser Asn Gly Gln Pro Glu Asn260 265 270Asn
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe275
280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
Trp Gln Gln Gly Asn290 295 300Val Phe Ser
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr305
310 315 320Gln Lys Ser Leu Ser Leu Ser
Pro Gly Lys325 330951327PRTArtificial SequenceSynthetic
951Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg1
5 10 15Ser Thr Ser Glu Ser Thr
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr20 25
30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser35
40 45Gly Val His Thr Phe Pro Ala Val Leu
Gln Ser Ser Gly Leu Tyr Ser50 55 60Leu
Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr65
70 75 80Tyr Thr Cys Asn Val Asp
His Lys Pro Ser Asn Thr Lys Val Asp Lys85 90
95Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro100
105 110Glu Phe Leu Gly Gly Pro Ser Val
Phe Leu Phe Pro Pro Lys Pro Lys115 120
125Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val130
135 140Asp Val Ser Gln Glu Asp Pro Glu Val
Gln Phe Asn Trp Tyr Val Asp145 150 155
160Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
Gln Phe165 170 175Asn Ser Thr Tyr Arg Val
Val Ser Val Leu Thr Val Leu His Gln Asp180 185
190Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
Leu195 200 205Pro Ser Ser Ile Glu Lys Thr
Ile Ser Lys Ala Lys Gly Gln Pro Arg210 215
220Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys225
230 235 240Asn Gln Val Ser
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp245 250
255Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
Tyr Lys260 265 270Thr Thr Pro Pro Val Leu
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser275 280
285Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
Ser290 295 300Cys Ser Val Met His Glu Ala
Leu His Asn His Tyr Thr Gln Lys Ser305 310
315 320Leu Ser Leu Ser Leu Gly Lys325952327PRTArtificial
SequenceSynthetic 952Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
Cys Ser Arg1 5 10 15Ser
Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr20
25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
Gly Ala Leu Thr Ser35 40 45Gly Val His
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser50 55
60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
Thr Lys Thr65 70 75
80Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys85
90 95Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys
Pro Pro Cys Pro Ala Pro100 105 110Glu Phe
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys115
120 125Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
Cys Val Val Val130 135 140Asp Val Ser Gln
Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp145 150
155 160Gly Val Glu Val His Asn Ala Lys Thr
Lys Pro Arg Glu Glu Gln Phe165 170 175Asn
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp180
185 190Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
Ser Asn Lys Gly Leu195 200 205Pro Ser Ser
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg210
215 220Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
Glu Met Thr Lys225 230 235
240Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp245
250 255Ile Ala Val Glu Trp Glu Ser Asn Gly
Gln Pro Glu Asn Asn Tyr Lys260 265 270Thr
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser275
280 285Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
Gly Asn Val Phe Ser290 295 300Cys Ser Val
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser305
310 315 320Leu Ser Leu Ser Leu Gly
Lys325953544PRTHomo sapiens 953Met Gly Ser Arg Cys Ala Leu Ala Leu Ala
Val Leu Ser Ala Leu Leu1 5 10
15Cys Gln Val Trp Ser Ser Gly Val Phe Glu Leu Lys Leu Gln Glu Phe20
25 30Val Asn Lys Lys Gly Leu Leu Gly Asn
Arg Asn Cys Cys Arg Gly Gly35 40 45Ala
Gly Pro Pro Pro Cys Ala Cys Arg Thr Phe Phe Arg Val Cys Leu50
55 60Lys His Tyr Gln Ala Ser Val Ser Pro Glu Pro
Pro Cys Thr Tyr Gly65 70 75
80Ser Ala Val Thr Pro Val Leu Gly Val Asp Ser Phe Ser Leu Pro Asp85
90 95Gly Gly Gly Ala Asp Ser Ala Phe Ser
Asn Pro Ile Arg Phe Pro Phe100 105 110Gly
Phe Thr Trp Pro Gly Thr Phe Ser Leu Ile Ile Glu Ala Leu His115
120 125Thr Asp Ser Pro Asp Asp Leu Ala Thr Glu Asn
Pro Glu Arg Leu Ile130 135 140Ser Arg Leu
Ala Thr Gln Arg His Leu Thr Val Gly Glu Glu Trp Ser145
150 155 160Gln Asp Leu His Ser Ser Gly
Arg Thr Asp Leu Lys Tyr Ser Tyr Arg165 170
175Phe Val Cys Asp Glu His Tyr Tyr Gly Glu Gly Cys Ser Val Phe Cys180
185 190Arg Pro Arg Asp Asp Ala Phe Gly His
Phe Thr Cys Gly Glu Arg Gly195 200 205Glu
Lys Val Cys Asn Pro Gly Trp Lys Gly Pro Tyr Cys Thr Glu Pro210
215 220Ile Cys Leu Pro Gly Cys Asp Glu Gln His Gly
Phe Cys Asp Lys Pro225 230 235
240Gly Glu Cys Lys Cys Arg Val Gly Trp Gln Gly Arg Tyr Cys Asp
Glu245 250 255Cys Ile Arg Tyr Pro Gly Cys
Leu His Gly Thr Cys Gln Gln Pro Trp260 265
270Gln Cys Asn Cys Gln Glu Gly Trp Gly Gly Leu Phe Cys Asn Gln Asp275
280 285Leu Asn Tyr Cys Thr His His Lys Pro
Cys Lys Asn Gly Ala Thr Cys290 295 300Thr
Asn Thr Gly Gln Gly Ser Tyr Thr Cys Ser Cys Arg Pro Gly Tyr305
310 315 320Thr Gly Ala Thr Cys Glu
Leu Gly Ile Asp Glu Cys Asp Pro Ser Pro325 330
335Cys Lys Asn Gly Gly Ser Cys Thr Asp Leu Glu Asn Ser Tyr Ser
Cys340 345 350Thr Cys Pro Pro Gly Phe Tyr
Gly Lys Ile Cys Glu Leu Ser Ala Met355 360
365Thr Cys Ala Asp Gly Pro Cys Phe Asn Gly Gly Arg Cys Ser Asp Ser370
375 380Pro Asp Gly Gly Tyr Ser Cys Arg Cys
Pro Val Gly Tyr Ser Gly Phe385 390 395
400Asn Cys Glu Lys Lys Ile Asp Tyr Cys Ser Ser Ser Pro Cys
Ser Asn405 410 415Gly Ala Lys Cys Val Asp
Leu Gly Asp Ala Tyr Leu Cys Arg Cys Gln420 425
430Ala Gly Phe Ser Gly Arg His Cys Asp Asp Asn Val Asp Asp Cys
Ala435 440 445Ser Ser Pro Cys Ala Asn Gly
Gly Thr Cys Arg Asp Gly Val Asn Asp450 455
460Phe Ser Cys Thr Cys Pro Pro Gly Tyr Thr Gly Arg Asn Cys Ser Ala465
470 475 480Pro Val Ser Arg
Cys Glu His Ala Pro Cys His Asn Gly Ala Thr Cys485 490
495His Glu Arg Gly His Arg Tyr Val Cys Glu Cys Ala Arg Gly
Tyr Gly500 505 510Gly Pro Asn Cys Gln Phe
Leu Leu Pro Glu Leu Pro Pro Gly Pro Ala515 520
525Val Val Asp Leu Thr Glu Lys Leu Glu Gly Gln Gly Gly Pro Phe
Pro530 535 540954490PRTHomo sapiens
954Met Val Ser Pro Arg Met Ser Gly Leu Leu Ser Gln Thr Val Ile Leu1
5 10 15Ala Leu Ile Phe Leu Pro
Gln Thr Arg Pro Ala Gly Val Phe Glu Leu20 25
30Gln Ile His Ser Phe Gly Pro Gly Pro Gly Pro Gly Ala Pro Arg Ser35
40 45Pro Cys Ser Ala Arg Leu Pro Cys Arg
Leu Phe Phe Arg Val Cys Leu50 55 60Lys
Pro Gly Leu Ser Glu Glu Ala Ala Glu Ser Pro Cys Ala Leu Gly65
70 75 80Ala Ala Leu Ser Ala Arg
Gly Pro Val Tyr Thr Glu Gln Pro Gly Ala85 90
95Pro Ala Pro Asp Leu Pro Leu Pro Asp Gly Leu Leu Gln Val Pro Phe100
105 110Arg Asp Ala Trp Pro Gly Thr Phe
Ser Phe Ile Ile Glu Thr Trp Arg115 120
125Glu Glu Leu Gly Asp Gln Ile Gly Gly Pro Ala Trp Ser Leu Leu Ala130
135 140Arg Val Ala Gly Arg Arg Arg Leu Ala
Ala Gly Gly Pro Trp Ala Arg145 150 155
160Asp Ile Gln Arg Ala Gly Ala Trp Glu Leu Arg Phe Ser Tyr
Arg Ala165 170 175Arg Cys Glu Pro Pro Ala
Val Gly Thr Ala Cys Thr Arg Leu Cys Arg180 185
190Pro Arg Ser Ala Pro Ser Arg Cys Gly Pro Gly Leu Arg Pro Cys
Ala195 200 205Pro Leu Glu Asp Glu Cys Glu
Ala Pro Pro Val Cys Arg Ala Gly Cys210 215
220Ser Pro Glu His Gly Phe Cys Glu Gln Pro Gly Glu Cys Arg Cys Leu225
230 235 240Glu Gly Trp Thr
Gly Pro Leu Cys Thr Val Pro Val Ser Thr Ser Ser245 250
255Cys Leu Ser Pro Arg Gly Pro Ser Ser Ala Thr Thr Gly Cys
Leu Val260 265 270Pro Gly Pro Gly Pro Cys
Asp Gly Asn Pro Cys Ala Asn Gly Gly Ser275 280
285Cys Ser Glu Thr Pro Arg Ser Phe Glu Cys Thr Cys Pro Arg Gly
Phe290 295 300Tyr Gly Leu Arg Cys Glu Val
Ser Gly Val Thr Cys Ala Asp Gly Pro305 310
315 320Cys Phe Asn Gly Gly Leu Cys Val Gly Gly Ala Asp
Pro Asp Ser Ala325 330 335Tyr Ile Cys His
Cys Pro Pro Gly Phe Gln Gly Ser Asn Cys Glu Lys340 345
350Arg Val Asp Arg Cys Ser Leu Gln Pro Cys Arg Asn Gly Gly
Leu Cys355 360 365Leu Asp Leu Gly His Ala
Leu Arg Cys Arg Cys Arg Ala Gly Phe Ala370 375
380Gly Pro Arg Cys Glu His Asp Leu Asp Asp Cys Ala Gly Arg Ala
Cys385 390 395 400Ala Asn
Gly Gly Thr Cys Val Glu Gly Gly Gly Ala His Arg Cys Ser405
410 415Cys Ala Leu Gly Phe Gly Gly Arg Asp Cys Arg Glu
Arg Ala Asp Pro420 425 430Cys Ala Ala Arg
Pro Cys Ala His Gly Gly Arg Cys Tyr Ala His Phe435 440
445Ser Gly Leu Val Cys Ala Cys Ala Pro Gly Tyr Met Gly Ala
Arg Cys450 455 460Glu Phe Pro Val His Pro
Asp Gly Ala Ser Ala Leu Pro Ala Ala Pro465 470
475 480Pro Gly Leu Arg Pro Gly Asp Pro Gln Arg485
490955527PRTMus musculus 955Met Thr Pro Ala Ser Arg Ser Ala
Cys Arg Trp Ala Leu Leu Leu Leu1 5 10
15Ala Val Leu Trp Pro Gln Gln Arg Ala Ala Gly Ser Gly Ile Phe
Gln20 25 30Leu Arg Leu Gln Glu Phe Val
Asn Gln Arg Gly Met Leu Ala Asn Gly35 40
45Gln Ser Cys Glu Pro Gly Cys Arg Thr Phe Phe Arg Ile Cys Leu Lys50
55 60His Phe Gln Ala Thr Phe Ser Glu Gly Pro
Cys Thr Phe Gly Asn Val65 70 75
80Ser Thr Pro Val Leu Gly Thr Asn Ser Phe Val Val Arg Asp Lys
Asn85 90 95Ser Gly Ser Gly Arg Asn Pro
Leu Gln Leu Pro Phe Asn Phe Thr Trp100 105
110Pro Gly Thr Phe Ser Leu Asn Ile Gln Ala Trp His Thr Pro Gly Asp115
120 125Asp Leu Arg Pro Glu Thr Ser Pro Gly
Asn Ser Leu Ile Ser Gln Ile130 135 140Ile
Ile Gln Gly Ser Leu Ala Val Gly Lys Ile Trp Arg Thr Asp Glu145
150 155 160Gln Asn Asp Thr Leu Thr
Arg Leu Ser Tyr Ser Tyr Arg Val Ile Cys165 170
175Ser Asp Asn Tyr Tyr Gly Glu Ser Cys Ser Arg Leu Cys Lys Lys
Arg180 185 190Asp Asp His Phe Gly His Tyr
Glu Cys Gln Pro Asp Gly Ser Leu Ser195 200
205Cys Leu Pro Gly Trp Thr Gly Lys Tyr Cys Asp Gln Pro Ile Cys Leu210
215 220Ser Gly Cys His Glu Gln Asn Gly Tyr
Cys Ser Lys Pro Asp Glu Cys225 230 235
240Ile Cys Arg Pro Gly Trp Gln Gly Arg Leu Cys Asn Glu Cys
Ile Pro245 250 255His Asn Gly Cys Arg His
Gly Thr Cys Ser Ile Pro Trp Gln Cys Ala260 265
270Cys Asp Glu Gly Trp Gly Gly Leu Phe Cys Asp Gln Asp Leu Asn
Tyr275 280 285Cys Thr His His Ser Pro Cys
Lys Asn Gly Ser Thr Cys Ser Asn Ser290 295
300Gly Pro Lys Gly Tyr Thr Cys Thr Cys Leu Pro Gly Tyr Thr Gly Glu305
310 315 320His Cys Glu Leu
Gly Leu Ser Lys Cys Ala Ser Asn Pro Cys Arg Asn325 330
335Gly Gly Ser Cys Lys Asp Gln Glu Asn Ser Tyr His Cys Leu
Cys Pro340 345 350Pro Gly Tyr Tyr Gly Gln
His Cys Glu His Ser Thr Leu Thr Cys Ala355 360
365Asp Ser Pro Cys Phe Asn Gly Gly Ser Cys Arg Glu Arg Asn Gln
Gly370 375 380Ser Ser Tyr Ala Cys Glu Cys
Pro Pro Asn Phe Thr Gly Ser Asn Cys385 390
395 400Glu Lys Lys Val Asp Arg Cys Thr Ser Asn Pro Cys
Ala Asn Gly Gly405 410 415Gln Cys Gln Asn
Arg Gly Pro Ser Arg Thr Cys Arg Cys Arg Pro Gly420 425
430Phe Thr Gly Thr His Cys Glu Leu His Ile Ser Asp Cys Ala
Arg Ser435 440 445Pro Cys Ala His Gly Gly
Thr Cys His Asp Leu Glu Asn Gly Pro Val450 455
460Cys Thr Cys Pro Ala Gly Phe Ser Gly Arg Arg Cys Glu Val Arg
Ile465 470 475 480Thr His
Asp Ala Cys Ala Ser Gly Pro Cys Phe Asn Gly Ala Thr Cys485
490 495Tyr Thr Gly Leu Ser Pro Asn Asn Phe Val Cys Asn
Cys Pro Tyr Gly500 505 510Phe Val Gly Ser
Arg Cys Glu Phe Pro Val Gly Leu Pro Pro Ser515 520
525956498PRTMacaca fascicularis 956Ser Gly Val Phe Gln Leu Gln
Leu Gln Glu Phe Val Asn Glu Arg Gly1 5 10
15Val Leu Ala Ser Gly Arg Pro Cys Glu Pro Gly Cys Arg Thr
Phe Phe20 25 30Arg Val Cys Leu Lys His
Phe Gln Ala Val Val Ser Pro Gly Pro Cys35 40
45Thr Phe Gly Ser Val Ser Thr Pro Val Leu Gly Thr Asn Ser Phe Ala50
55 60Val Arg Asp Asp Ser Ser Gly Gly Gly
Arg Asn Pro Leu Gln Leu Pro65 70 75
80Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu Ile Ile Glu
Ala Trp85 90 95His Ala Pro Gly Asp Asp
Leu Arg Pro Glu Ala Leu Pro Pro Asp Ala100 105
110Leu Ile Ser Lys Ile Ala Ile Gln Gly Ser Leu Ala Val Gly Gln
Asn115 120 125Trp Leu Leu Asp Glu Gln Thr
Ser Thr Leu Thr Arg Leu Arg Tyr Ser130 135
140Tyr Arg Val Ile Cys Ser Asp Asn Tyr Tyr Gly Asp Asn Cys Ser Arg145
150 155 160Leu Cys Lys Lys
Arg Asn Asp His Phe Gly His Tyr Val Cys Gln Pro165 170
175Asp Gly Asn Leu Ser Cys Leu Pro Gly Trp Thr Gly Glu Tyr
Cys Gln180 185 190Gln Pro Ile Cys Leu Ser
Gly Cys His Glu Gln Asn Gly Tyr Cys Ser195 200
205Lys Pro Ala Glu Cys Leu Cys Arg Pro Gly Trp Gln Gly Arg Leu
Cys210 215 220Asn Glu Cys Ile Pro His Asn
Gly Cys Arg His Gly Thr Cys Ser Thr225 230
235 240Pro Trp Gln Cys Thr Cys Asp Glu Gly Trp Gly Gly
Leu Phe Cys Asp245 250 255Gln Asp Leu Asn
Tyr Cys Thr His His Ser Pro Cys Lys Asn Gly Ala260 265
270Thr Cys Ser Asn Ser Gly Gln Arg Ser Tyr Thr Cys Thr Cys
Arg Pro275 280 285Gly Tyr Thr Gly Val Asp
Cys Glu Leu Glu Leu Ser Glu Cys Asp Ser290 295
300Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu Asp Gly
Tyr305 310 315 320His Cys
Leu Cys Pro Pro Gly Tyr Tyr Gly Leu His Cys Glu His Ser325
330 335Thr Leu Ser Cys Ala Asp Ser Pro Cys Phe Asn Gly
Gly Ser Cys Arg340 345 350Glu Arg Asn Gln
Gly Ala Ser Tyr Ala Cys Glu Cys Pro Pro Asn Phe355 360
365Thr Gly Ser Asn Cys Glu Lys Lys Val Asp Arg Cys Thr Ser
Asn Pro370 375 380Cys Ala Asn Gly Gly Gln
Cys Leu Asn Arg Gly Pro Ser Arg Met Cys385 390
395 400Arg Cys Arg Pro Gly Phe Thr Gly Thr Tyr Cys
Glu Arg His Val Ser405 410 415Asp Cys Ala
Arg Asn Pro Cys Ala His Gly Gly Thr Cys His Asp Leu420
425 430Glu Ser Gly Leu Met Cys Thr Cys Pro Ala Gly Phe
Ser Gly Arg Arg435 440 445Cys Glu Val Arg
Thr Ser Ile Asp Ala Cys Ala Ser Ser Pro Cys Phe450 455
460Asn Arg Ala Thr Cys Tyr Thr Asp Leu Ser Thr Asp Thr Phe
Val Cys465 470 475 480Asn
Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe Pro Met Gly485
490 495Leu Pro957498PRTMacaca mulatta 957Ser Gly Val
Phe Gln Leu Gln Leu Gln Glu Phe Val Asn Glu Arg Gly1 5
10 15Val Leu Ala Ser Gly Arg Pro Cys Glu Pro
Gly Cys Arg Thr Phe Phe20 25 30Arg Val
Cys Leu Lys His Phe Gln Ala Val Val Ser Pro Gly Pro Cys35
40 45Thr Phe Gly Ser Val Ser Thr Pro Val Leu Gly Thr
Asn Ser Phe Ala50 55 60Val Arg Asp Asp
Ser Ser Gly Gly Gly Arg Asn Pro Leu Gln Leu Pro65 70
75 80Phe Asn Phe Thr Trp Pro Gly Thr Phe
Ser Leu Ile Ile Glu Ala Trp85 90 95His
Ala Pro Gly Asp Asp Leu Arg Pro Glu Ala Leu Pro Pro Asp Ala100
105 110Leu Ile Ser Lys Ile Ala Ile Gln Gly Ser Leu
Ala Val Gly Gln Asn115 120 125Trp Leu Leu
Asp Glu Gln Thr Ser Thr Leu Thr Arg Leu Arg Tyr Ser130
135 140Tyr Arg Val Ile Cys Ser Asp Asn Tyr Tyr Gly Asp
Asn Cys Ser Arg145 150 155
160Leu Cys Lys Lys Arg Asn Asp His Phe Gly His Tyr Val Cys Gln Pro165
170 175Asp Gly Asn Leu Ser Cys Leu Pro Gly
Trp Thr Gly Glu Tyr Cys Gln180 185 190Gln
Pro Ile Cys Leu Ser Gly Cys His Glu Gln Asn Gly Tyr Cys Ser195
200 205Lys Pro Ala Glu Cys Leu Cys Arg Pro Gly Trp
Gln Gly Arg Leu Cys210 215 220Asn Glu Cys
Ile Pro His Asn Gly Cys Arg His Gly Thr Cys Ser Thr225
230 235 240Pro Trp Gln Cys Thr Cys Asp
Glu Gly Trp Gly Gly Leu Phe Cys Asp245 250
255Gln Asp Leu Asn Tyr Cys Thr His His Ser Pro Cys Lys Asn Gly Ala260
265 270Thr Cys Ser Asn Ser Gly Gln Arg Ser
Tyr Thr Cys Thr Cys Arg Pro275 280 285Gly
Tyr Thr Gly Val Asp Cys Glu Leu Glu Leu Ser Glu Cys Asp Ser290
295 300Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp
Gln Glu Asp Gly Tyr305 310 315
320His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Leu His Cys Glu His
Ser325 330 335Thr Leu Ser Cys Ala Asp Ser
Pro Cys Phe Asn Gly Gly Ser Cys Arg340 345
350Glu Arg Asn Gln Gly Ala Ser Tyr Ala Cys Glu Cys Pro Pro Asn Phe355
360 365Thr Gly Ser Asn Cys Glu Lys Lys Val
Asp Arg Cys Thr Ser Asn Pro370 375 380Cys
Ala Asn Gly Gly Gln Cys Leu Asn Arg Gly Pro Ser Arg Met Cys385
390 395 400Arg Cys Arg Pro Gly Phe
Thr Gly Thr Tyr Cys Glu Arg His Val Ser405 410
415Asp Cys Ala Arg Asn Pro Cys Ala His Gly Gly Thr Cys His Asp
Leu420 425 430Glu Ser Gly Leu Met Cys Thr
Cys Pro Ala Gly Phe Ser Gly Arg Arg435 440
445Cys Glu Val Arg Thr Ser Ile Asp Ala Cys Ala Ser Ser Pro Cys Phe450
455 460Asn Arg Ala Thr Cys Tyr Thr Asp Leu
Ser Thr Asp Thr Phe Val Cys465 470 475
480Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe Pro
Val Gly485 490 495Leu Pro
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