MXPA00009434A - Serine protease variants having amino acid substitutions - Google Patents
Serine protease variants having amino acid substitutionsInfo
- Publication number
- MXPA00009434A MXPA00009434A MXPA/A/2000/009434A MXPA00009434A MXPA00009434A MX PA00009434 A MXPA00009434 A MX PA00009434A MX PA00009434 A MXPA00009434 A MX PA00009434A MX PA00009434 A MXPA00009434 A MX PA00009434A
- Authority
- MX
- Mexico
- Prior art keywords
- leu
- val
- asn
- met
- thr
- Prior art date
Links
- 238000006467 substitution reaction Methods 0.000 title claims abstract description 90
- 108010022999 Serine Proteases Proteins 0.000 title claims abstract description 26
- 102000012479 Serine Proteases Human genes 0.000 title claims abstract description 26
- 150000001413 amino acids Chemical group 0.000 title claims description 44
- 239000000203 mixture Substances 0.000 claims abstract description 128
- 238000004140 cleaning Methods 0.000 claims abstract description 70
- 102000035443 Peptidases Human genes 0.000 claims abstract description 37
- 108091005771 Peptidases Proteins 0.000 claims abstract description 37
- 108090000787 Subtilisin Proteins 0.000 claims abstract description 22
- 230000000875 corresponding Effects 0.000 claims abstract description 17
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims description 456
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims description 343
- MTCFGRXMJLQNBG-REOHCLBHSA-N L-serine Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 231
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 180
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims description 147
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 131
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 120
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims description 100
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 75
- 125000000510 L-tryptophano group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C(C([H])([H])[C@@]([H])(C(O[H])=O)N([H])[*])C2=C1[H] 0.000 claims description 61
- XUJNEKJLAYXESH-REOHCLBHSA-N L-cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 60
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims description 56
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 55
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 claims description 54
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 50
- -1 substituent amino acid Chemical class 0.000 claims description 19
- 230000035772 mutation Effects 0.000 claims description 18
- 235000019833 protease Nutrition 0.000 claims description 17
- 230000000087 stabilizing Effects 0.000 claims description 7
- 102220384186 UMAD1 Q19E Human genes 0.000 claims description 2
- 101700024251 apr Proteins 0.000 claims description 2
- 101710018965 subC Proteins 0.000 claims description 2
- 125000000393 L-methionino group Chemical group [H]OC(=O)[C@@]([H])(N([H])[*])C([H])([H])C(SC([H])([H])[H])([H])[H] 0.000 claims 30
- 125000000267 glycino group Chemical group [H]N([*])C([H])([H])C(=O)O[H] 0.000 claims 23
- 125000003275 alpha amino acid group Chemical class 0.000 abstract description 49
- 239000004365 Protease Substances 0.000 abstract description 36
- 230000003247 decreasing Effects 0.000 abstract description 6
- BQBCIBCLXBKYHW-CSMHCCOUSA-N Thr-Leu Chemical compound CC(C)C[C@@H](C([O-])=O)NC(=O)[C@@H]([NH3+])[C@@H](C)O BQBCIBCLXBKYHW-CSMHCCOUSA-N 0.000 description 389
- KRBMQYPTDYSENE-BQBZGAKWSA-N His-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H](N)CC1=CNC=N1 KRBMQYPTDYSENE-BQBZGAKWSA-N 0.000 description 276
- 108010018006 histidylserine Proteins 0.000 description 276
- 229920003245 polyoctenamer Polymers 0.000 description 250
- RFCVXVPWSPOMFJ-UHFFFAOYSA-N 2-[(2-azaniumyl-3-phenylpropanoyl)amino]-4-methylpentanoate Chemical compound CC(C)CC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 RFCVXVPWSPOMFJ-UHFFFAOYSA-N 0.000 description 160
- 108010073101 phenylalanylleucine Proteins 0.000 description 160
- MMFKFJORZBJVNF-UWVGGRQHSA-N His-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](N)CC1=CN=CN1 MMFKFJORZBJVNF-UWVGGRQHSA-N 0.000 description 139
- 108010025306 histidylleucine Proteins 0.000 description 139
- JMEWFDUAFKVAAT-UHFFFAOYSA-N Methionyl-Asparagine Chemical compound CSCCC(N)C(=O)NC(C(O)=O)CC(N)=O JMEWFDUAFKVAAT-UHFFFAOYSA-N 0.000 description 130
- AUEJLPRZGVVDNU-STQMWFEESA-N Tyr-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 AUEJLPRZGVVDNU-STQMWFEESA-N 0.000 description 123
- 108010078580 tyrosylleucine Proteins 0.000 description 123
- MDSUKZSLOATHMH-IUCAKERBSA-N Leu-Val Chemical compound CC(C)C[C@H]([NH3+])C(=O)N[C@@H](C(C)C)C([O-])=O MDSUKZSLOATHMH-IUCAKERBSA-N 0.000 description 105
- WITCOKQIPFWQQD-FSPLSTOPSA-N Val-Asn Chemical compound CC(C)[C@H](N)C(=O)N[C@H](C(O)=O)CC(N)=O WITCOKQIPFWQQD-FSPLSTOPSA-N 0.000 description 104
- BJFJQOMZCSHBMY-YUMQZZPRSA-N Met-Val Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C(C)C)C(O)=O BJFJQOMZCSHBMY-YUMQZZPRSA-N 0.000 description 99
- KRNYOVHEKOBTEF-YUMQZZPRSA-N Val-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(O)=O KRNYOVHEKOBTEF-YUMQZZPRSA-N 0.000 description 80
- 108010021889 valylvaline Proteins 0.000 description 80
- LCPYQJIKPJDLLB-UWVGGRQHSA-N Leu-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(O)=O)CC(C)C LCPYQJIKPJDLLB-UWVGGRQHSA-N 0.000 description 79
- 108010091798 leucylleucine Proteins 0.000 description 79
- STTYIMSDIYISRG-WDSKDSINSA-N Val-Ser Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(O)=O STTYIMSDIYISRG-WDSKDSINSA-N 0.000 description 70
- PBOUVYGPDSARIS-IUCAKERBSA-N Met-Leu Chemical compound CSCC[C@H](N)C(=O)N[C@H](C(O)=O)CC(C)C PBOUVYGPDSARIS-IUCAKERBSA-N 0.000 description 69
- CKHWEVXPLJBEOZ-UHFFFAOYSA-N Threoninyl-Valine Chemical compound CC(C)C(C(O)=O)NC(=O)C(N)C(C)O CKHWEVXPLJBEOZ-UHFFFAOYSA-N 0.000 description 69
- XCTHZFGSVQBHBW-IUCAKERBSA-N Val-Leu Chemical compound CC(C)C[C@@H](C([O-])=O)NC(=O)[C@@H]([NH3+])C(C)C XCTHZFGSVQBHBW-IUCAKERBSA-N 0.000 description 62
- 108010036320 valylleucine Proteins 0.000 description 62
- WSDOHRLQDGAOGU-UHFFFAOYSA-N Histidinyl-Asparagine Chemical compound NC(=O)CC(C(O)=O)NC(=O)C(N)CC1=CN=CN1 WSDOHRLQDGAOGU-UHFFFAOYSA-N 0.000 description 51
- UQTNIFUCMBFWEJ-UHFFFAOYSA-N Threoninyl-Asparagine Chemical compound CC(O)C(N)C(=O)NC(C(O)=O)CC(N)=O UQTNIFUCMBFWEJ-UHFFFAOYSA-N 0.000 description 50
- MQLZLIYPFDIDMZ-UHFFFAOYSA-N Asparaginyl-Isoleucine Chemical compound CCC(C)C(C(O)=O)NC(=O)C(N)CC(N)=O MQLZLIYPFDIDMZ-UHFFFAOYSA-N 0.000 description 30
- HZYHBDVRCBDJJV-HAFWLYHUSA-N Ile-Asn Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@H](C(O)=O)CC(N)=O HZYHBDVRCBDJJV-HAFWLYHUSA-N 0.000 description 30
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 30
- FMIIKPHLJKUXGE-GUBZILKMSA-N Lys-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H](N)CCCCN FMIIKPHLJKUXGE-GUBZILKMSA-N 0.000 description 28
- BXNGIHFNNNSEOS-UWVGGRQHSA-N Phe-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 BXNGIHFNNNSEOS-UWVGGRQHSA-N 0.000 description 25
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 25
- IDXZDKMBEXLFMB-UHFFFAOYSA-N Histidinyl-Isoleucine Chemical compound CCC(C)C(C(O)=O)NC(=O)C(N)CC1=CN=CN1 IDXZDKMBEXLFMB-UHFFFAOYSA-N 0.000 description 23
- WEDDFMCSUNNZJR-WDSKDSINSA-N Met-Ser Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CO)C(O)=O WEDDFMCSUNNZJR-WDSKDSINSA-N 0.000 description 23
- ROHDXJUFQVRDAV-UWVGGRQHSA-N Phe-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 ROHDXJUFQVRDAV-UWVGGRQHSA-N 0.000 description 23
- 108010051242 phenylalanylserine Proteins 0.000 description 23
- QYLJIYOGHRGUIH-CIUDSAMLSA-N Arg-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H](N)CCCNC(N)=N QYLJIYOGHRGUIH-CIUDSAMLSA-N 0.000 description 22
- GXDLGHLJTHMDII-WISUUJSJSA-N Thr-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CO)C(O)=O GXDLGHLJTHMDII-WISUUJSJSA-N 0.000 description 22
- BSWHERGFUNMWGS-UHFFFAOYSA-N Aspartyl-Isoleucine Chemical compound CCC(C)C(C(O)=O)NC(=O)C(N)CC(O)=O BSWHERGFUNMWGS-UHFFFAOYSA-N 0.000 description 20
- KWBQPGIYEZKDEG-FSPLSTOPSA-N Asn-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H](N)CC(N)=O KWBQPGIYEZKDEG-FSPLSTOPSA-N 0.000 description 19
- 102000004190 Enzymes Human genes 0.000 description 16
- 108090000790 Enzymes Proteins 0.000 description 16
- YQAIUOWPSUOINN-IUCAKERBSA-N Lys-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H](N)CCCCN YQAIUOWPSUOINN-IUCAKERBSA-N 0.000 description 16
- OYOQKMOWUDVWCR-RYUDHWBXSA-N Tyr-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OYOQKMOWUDVWCR-RYUDHWBXSA-N 0.000 description 16
- 108010017391 lysylvaline Proteins 0.000 description 15
- 235000018102 proteins Nutrition 0.000 description 15
- 102000004169 proteins and genes Human genes 0.000 description 15
- 108090000623 proteins and genes Proteins 0.000 description 15
- 239000004094 surface-active agent Substances 0.000 description 14
- 229940088598 Enzyme Drugs 0.000 description 13
- ONWMQORSVZYVNH-UHFFFAOYSA-N Tyrosyl-Asparagine Chemical compound NC(=O)CC(C(O)=O)NC(=O)C(N)CC1=CC=C(O)C=C1 ONWMQORSVZYVNH-UHFFFAOYSA-N 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- ZSXJENBJGRHKIG-UHFFFAOYSA-N Tyrosyl-Serine Chemical compound OCC(C(O)=O)NC(=O)C(N)CC1=CC=C(O)C=C1 ZSXJENBJGRHKIG-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- 239000007788 liquid Substances 0.000 description 12
- 210000003491 Skin Anatomy 0.000 description 11
- LUMXICQAOKVQOB-UHFFFAOYSA-N Threoninyl-Isoleucine Chemical compound CCC(C)C(C(O)=O)NC(=O)C(N)C(C)O LUMXICQAOKVQOB-UHFFFAOYSA-N 0.000 description 11
- QJKMCQRFHJRIPU-XDTLVQLUSA-N Tyr-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 QJKMCQRFHJRIPU-XDTLVQLUSA-N 0.000 description 11
- 210000004027 cells Anatomy 0.000 description 11
- ATIPDCIQTUXABX-UWVGGRQHSA-N Lys-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](N)CCCCN ATIPDCIQTUXABX-UWVGGRQHSA-N 0.000 description 10
- 239000003599 detergent Substances 0.000 description 10
- VLDVBZICYBVQHB-IUCAKERBSA-N His-Val Chemical compound CC(C)[C@@H](C([O-])=O)NC(=O)[C@@H]([NH3+])CC1=CN=CN1 VLDVBZICYBVQHB-IUCAKERBSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- XITLYYAIPBBHPX-UHFFFAOYSA-N γ-glutamyl-Isoleucine Chemical compound CCC(C)C(C(O)=O)NC(=O)C(N)CCC(N)=O XITLYYAIPBBHPX-UHFFFAOYSA-N 0.000 description 9
- 239000002537 cosmetic Substances 0.000 description 8
- 238000004851 dishwashing Methods 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 239000002453 shampoo Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- WYBVBIHNJWOLCJ-IUCAKERBSA-N Arg-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](N)CCCNC(N)=N WYBVBIHNJWOLCJ-IUCAKERBSA-N 0.000 description 7
- CPMKYMGGYUFOHS-FSPLSTOPSA-N Asp-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H](N)CC(O)=O CPMKYMGGYUFOHS-FSPLSTOPSA-N 0.000 description 7
- HXWUJJADFMXNKA-UHFFFAOYSA-N Asparaginyl-Leucine Chemical compound CC(C)CC(C(O)=O)NC(=O)C(N)CC(N)=O HXWUJJADFMXNKA-UHFFFAOYSA-N 0.000 description 7
- ARPVSMCNIDAQBO-UHFFFAOYSA-N Glutaminyl-Leucine Chemical compound CC(C)CC(C(O)=O)NC(=O)C(N)CCC(N)=O ARPVSMCNIDAQBO-UHFFFAOYSA-N 0.000 description 7
- 125000000539 amino acid group Chemical group 0.000 description 7
- 239000004744 fabric Substances 0.000 description 7
- 239000000499 gel Substances 0.000 description 7
- ZVDPYSVOZFINEE-UHFFFAOYSA-N Aspartyl-Leucine Chemical compound CC(C)CC(C(O)=O)NC(=O)C(N)CC(O)=O ZVDPYSVOZFINEE-UHFFFAOYSA-N 0.000 description 6
- KWIUHFFTVRNATP-UHFFFAOYSA-N Betaine Natural products C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 6
- 239000000427 antigen Substances 0.000 description 6
- 102000038129 antigens Human genes 0.000 description 6
- 108091007172 antigens Proteins 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- DAQIJMOLTMGJLO-YUMQZZPRSA-N Arg-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H](N)CCCNC(N)=N DAQIJMOLTMGJLO-YUMQZZPRSA-N 0.000 description 5
- 240000008371 Bacillus subtilis Species 0.000 description 5
- 229940075615 Bacillus subtilis Drugs 0.000 description 5
- 235000014469 Bacillus subtilis Nutrition 0.000 description 5
- MLTRLIITQPXHBJ-BQBZGAKWSA-N Leu-Asn Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(O)=O)CC(N)=O MLTRLIITQPXHBJ-BQBZGAKWSA-N 0.000 description 5
- 239000007983 Tris buffer Substances 0.000 description 5
- 108010036533 arginylvaline Proteins 0.000 description 5
- 229920003013 deoxyribonucleic acid Polymers 0.000 description 5
- 230000001815 facial Effects 0.000 description 5
- 238000005187 foaming Methods 0.000 description 5
- 230000028993 immune response Effects 0.000 description 5
- 238000002703 mutagenesis Methods 0.000 description 5
- 231100000350 mutagenesis Toxicity 0.000 description 5
- 229940031012 ANTI-ACNE PREPARATIONS Drugs 0.000 description 4
- RJUHZPRQRQLCFL-IMJSIDKUSA-N Asn-Asn Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CC(N)=O)C(O)=O RJUHZPRQRQLCFL-IMJSIDKUSA-N 0.000 description 4
- 102200119766 CEACAM3 G70V Human genes 0.000 description 4
- XGDCYUQSFDQISZ-BQBZGAKWSA-N Leu-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(O)=O XGDCYUQSFDQISZ-BQBZGAKWSA-N 0.000 description 4
- 229960004063 Propylene glycol Drugs 0.000 description 4
- 102100008254 SELL Human genes 0.000 description 4
- 108010056079 Subtilisins Proteins 0.000 description 4
- 102000005158 Subtilisins Human genes 0.000 description 4
- 230000002009 allergen Effects 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000000855 fermentation Methods 0.000 description 4
- 230000004151 fermentation Effects 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 230000001900 immune effect Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000002609 media Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 235000013772 propylene glycol Nutrition 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- CXISPYVYMQWFLE-VKHMYHEASA-N Ala-Gly Chemical compound C[C@H]([NH3+])C(=O)NCC([O-])=O CXISPYVYMQWFLE-VKHMYHEASA-N 0.000 description 3
- 229940110715 ENZYMES FOR TREATMENT OF WOUNDS AND ULCERS Drugs 0.000 description 3
- 241000588724 Escherichia coli Species 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- TWVKGYNQQAUNRN-ACZMJKKPSA-N Ile-Ser Chemical compound CC[C@H](C)[C@H]([NH3+])C(=O)N[C@@H](CO)C([O-])=O TWVKGYNQQAUNRN-ACZMJKKPSA-N 0.000 description 3
- 241000880493 Leptailurus serval Species 0.000 description 3
- 239000004909 Moisturizer Substances 0.000 description 3
- 102200015648 PPP4C N76D Human genes 0.000 description 3
- 206010070834 Sensitisation Diseases 0.000 description 3
- WOUIMBGNEUWXQG-VKHMYHEASA-N Ser-Gly Chemical compound OC[C@H](N)C(=O)NCC(O)=O WOUIMBGNEUWXQG-VKHMYHEASA-N 0.000 description 3
- NFDYGNFETJVMSE-BQBZGAKWSA-N Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](N)CO NFDYGNFETJVMSE-BQBZGAKWSA-N 0.000 description 3
- ILVGMCVCQBJPSH-WDSKDSINSA-N Ser-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H](N)CO ILVGMCVCQBJPSH-WDSKDSINSA-N 0.000 description 3
- 210000000515 Tooth Anatomy 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 108010047495 alanylglycine Proteins 0.000 description 3
- 230000000172 allergic Effects 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 201000008937 atopic dermatitis Diseases 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000000975 dye Substances 0.000 description 3
- 238000010353 genetic engineering Methods 0.000 description 3
- 108010089804 glycyl-threonine Proteins 0.000 description 3
- 108010037850 glycylvaline Proteins 0.000 description 3
- 229940020899 hematological Enzymes Drugs 0.000 description 3
- 239000006210 lotion Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 230000001333 moisturizer Effects 0.000 description 3
- 230000002797 proteolythic Effects 0.000 description 3
- 230000008313 sensitization Effects 0.000 description 3
- 230000001235 sensitizing Effects 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VNYDHJARLHNEGA-RYUDHWBXSA-N (2S)-1-[(2S)-2-azaniumyl-3-(4-hydroxyphenyl)propanoyl]pyrrolidine-2-carboxylate Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(O)=O)C1=CC=C(O)C=C1 VNYDHJARLHNEGA-RYUDHWBXSA-N 0.000 description 2
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-Propanediol Chemical compound OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 2
- SONUFGRSSMFHFN-IMJSIDKUSA-N Asn-Ser Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CO)C(O)=O SONUFGRSSMFHFN-IMJSIDKUSA-N 0.000 description 2
- 210000004369 Blood Anatomy 0.000 description 2
- 101710011563 CL401 Proteins 0.000 description 2
- 101700070276 CRSP Proteins 0.000 description 2
- MRVYVEQPNDSWLH-UHFFFAOYSA-N Glutaminyl-Valine Chemical compound CC(C)C(C(O)=O)NC(=O)C(N)CCC(N)=O MRVYVEQPNDSWLH-UHFFFAOYSA-N 0.000 description 2
- FUESBOMYALLFNI-VKHMYHEASA-N Gly-Asn Chemical compound NCC(=O)N[C@H](C(O)=O)CC(N)=O FUESBOMYALLFNI-VKHMYHEASA-N 0.000 description 2
- OLIFSFOFKGKIRH-WUJLRWPWSA-N Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CN OLIFSFOFKGKIRH-WUJLRWPWSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- LESXFEZIFXFIQR-LURJTMIESA-N Leu-Gly Chemical compound CC(C)C[C@H](N)C(=O)NCC(O)=O LESXFEZIFXFIQR-LURJTMIESA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- OGGRSJFVXREKOR-CIUDSAMLSA-N Met-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H](N)CCSC OGGRSJFVXREKOR-CIUDSAMLSA-N 0.000 description 2
- 102200015164 PYCARD V72A Human genes 0.000 description 2
- IEHDJWSAXBGJIP-RYUDHWBXSA-N Phe-Val Chemical compound CC(C)[C@@H](C([O-])=O)NC(=O)[C@@H]([NH3+])CC1=CC=CC=C1 IEHDJWSAXBGJIP-RYUDHWBXSA-N 0.000 description 2
- 101710038663 SELL Proteins 0.000 description 2
- YZMPDHTZJJCGEI-BQBZGAKWSA-N Ser-His Chemical compound OC[C@H](N)C(=O)N[C@H](C(O)=O)CC1=CNC=N1 YZMPDHTZJJCGEI-BQBZGAKWSA-N 0.000 description 2
- PBUXMVYWOSKHMF-WDSKDSINSA-N Ser-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@@H](N)CO PBUXMVYWOSKHMF-WDSKDSINSA-N 0.000 description 2
- 101710039019 TK1689 Proteins 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- PNVLWFYAPWAQMU-CIUDSAMLSA-N Val-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H](N)C(C)C PNVLWFYAPWAQMU-CIUDSAMLSA-N 0.000 description 2
- 239000002250 absorbent Substances 0.000 description 2
- 230000002745 absorbent Effects 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 108010087924 alanylproline Proteins 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 125000000129 anionic group Chemical group 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 235000011148 calcium chloride Nutrition 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000005018 casein Substances 0.000 description 2
- 235000021240 caseins Nutrition 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 101700021779 fls Proteins 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000000670 limiting Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 239000006072 paste Substances 0.000 description 2
- 108010084572 phenylalanyl-valine Proteins 0.000 description 2
- 108010031719 prolyl-serine Proteins 0.000 description 2
- 108010029020 prolylglycine Proteins 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 108010048818 seryl-histidine Proteins 0.000 description 2
- 108010071207 serylmethionine Proteins 0.000 description 2
- 239000000344 soap Substances 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- IOUPEELXVYPCPG-UHFFFAOYSA-N val-gly Chemical compound CC(C)C(N)C(=O)NCC(O)=O IOUPEELXVYPCPG-UHFFFAOYSA-N 0.000 description 2
- 108010073969 valyllysine Proteins 0.000 description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (-)-propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- KXCADYRCLIEADB-QRPNPIFTSA-N (2S)-2-amino-3-phenylpropanoic acid;4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1.OC(=O)[C@@H](N)CC1=CC=CC=C1 KXCADYRCLIEADB-QRPNPIFTSA-N 0.000 description 1
- DDPKBJZLAXLQGZ-KBIXCLLPSA-N (3S)-3-[[(2S)-2-[[(2S)-2-aminopropanoyl]amino]-3-methylbutanoyl]amino]-4-[[(1S)-1-carboxy-2-hydroxyethyl]amino]-4-oxobutanoic acid Chemical compound C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O DDPKBJZLAXLQGZ-KBIXCLLPSA-N 0.000 description 1
- CUVLMZNMSPJDON-UHFFFAOYSA-N 1-(1-butoxypropan-2-yloxy)propan-2-ol Chemical compound CCCCOCC(C)OCC(C)O CUVLMZNMSPJDON-UHFFFAOYSA-N 0.000 description 1
- IPDRTIBDOPMMIQ-VAOFZXAKSA-N 1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)-2-methyloxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1[C@]1(C)O[C@H](CO)[C@@H](O)C1 IPDRTIBDOPMMIQ-VAOFZXAKSA-N 0.000 description 1
- RWNUSVWFHDHRCJ-UHFFFAOYSA-N 1-butoxypropan-2-ol Chemical compound CCCCOCC(C)O RWNUSVWFHDHRCJ-UHFFFAOYSA-N 0.000 description 1
- JCTXKRPTIMZBJT-UHFFFAOYSA-N 2,2,4-trimethylpentane-1,3-diol Chemical compound CC(C)C(O)C(C)(C)CO JCTXKRPTIMZBJT-UHFFFAOYSA-N 0.000 description 1
- MPJQXAIKMSKXBI-UHFFFAOYSA-N 2,7,9,14-tetraoxa-1,8-diazabicyclo[6.6.2]hexadecane-3,6,10,13-tetrone Chemical class C1CN2OC(=O)CCC(=O)ON1OC(=O)CCC(=O)O2 MPJQXAIKMSKXBI-UHFFFAOYSA-N 0.000 description 1
- GJSURZIOUXUGAL-UHFFFAOYSA-N 2-((2,6-Dichlorophenyl)imino)imidazolidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- CFPOJWPDQWJEMO-UHFFFAOYSA-J 2-(1,2-dicarboxylatoethoxy)butanedioate Chemical class [O-]C(=O)CC(C([O-])=O)OC(C([O-])=O)CC([O-])=O CFPOJWPDQWJEMO-UHFFFAOYSA-J 0.000 description 1
- OAYXUHPQHDHDDZ-UHFFFAOYSA-N 2-(2-butoxyethoxy)ethanol Chemical compound CCCCOCCOCCO OAYXUHPQHDHDDZ-UHFFFAOYSA-N 0.000 description 1
- GZMAAYIALGURDQ-UHFFFAOYSA-N 2-(2-hexoxyethoxy)ethanol Chemical compound CCCCCCOCCOCCO GZMAAYIALGURDQ-UHFFFAOYSA-N 0.000 description 1
- POAOYUHQDCAZBD-UHFFFAOYSA-N 2-Butoxyethanol Chemical compound CCCCOCCO POAOYUHQDCAZBD-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- UPGSWASWQBLSKZ-UHFFFAOYSA-N 2-hexoxyethanol Chemical compound CCCCCCOCCO UPGSWASWQBLSKZ-UHFFFAOYSA-N 0.000 description 1
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-Nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 1
- TUTIHHSZKFBMHM-UHFFFAOYSA-N 4-amino-5-[(3-amino-1-carboxy-3-oxopropyl)amino]-5-oxopentanoic acid Chemical compound OC(=O)CCC(N)C(=O)NC(CC(N)=O)C(O)=O TUTIHHSZKFBMHM-UHFFFAOYSA-N 0.000 description 1
- 101710006356 ACTI Proteins 0.000 description 1
- HJCMDXDYPOUFDY-WHFBIAKZSA-N Ala-Gln Chemical compound C[C@H](N)C(=O)N[C@H](C(O)=O)CCC(N)=O HJCMDXDYPOUFDY-WHFBIAKZSA-N 0.000 description 1
- WPWUFUBLGADILS-WDSKDSINSA-N Ala-Pro Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(O)=O WPWUFUBLGADILS-WDSKDSINSA-N 0.000 description 1
- IPWKGIFRRBGCJO-IMJSIDKUSA-N Ala-Ser Chemical compound C[C@H]([NH3+])C(=O)N[C@@H](CO)C([O-])=O IPWKGIFRRBGCJO-IMJSIDKUSA-N 0.000 description 1
- MGRVRXRGTBOSHW-UHFFFAOYSA-N Aminomethylphosphonic acid Chemical class NCP(O)(O)=O MGRVRXRGTBOSHW-UHFFFAOYSA-N 0.000 description 1
- 229940025131 Amylases Drugs 0.000 description 1
- 102000013142 Amylases Human genes 0.000 description 1
- 108010065511 Amylases Proteins 0.000 description 1
- IJYZHIOOBGIINM-WDSKDSINSA-N Arg-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H](N)CCCN=C(N)N IJYZHIOOBGIINM-WDSKDSINSA-N 0.000 description 1
- JSLGXODUIAFWCF-UHFFFAOYSA-N Arginyl-Asparagine Chemical compound NC(N)=NCCCC(N)C(=O)NC(CC(N)=O)C(O)=O JSLGXODUIAFWCF-UHFFFAOYSA-N 0.000 description 1
- QCWJKJLNCFEVPQ-WHFBIAKZSA-N Asn-Gln Chemical compound NC(=O)C[C@H](N)C(=O)N[C@H](C(O)=O)CCC(N)=O QCWJKJLNCFEVPQ-WHFBIAKZSA-N 0.000 description 1
- KLKHFFMNGWULBN-VKHMYHEASA-N Asn-Gly Chemical compound NC(=O)C[C@H](N)C(=O)NCC(O)=O KLKHFFMNGWULBN-VKHMYHEASA-N 0.000 description 1
- JHFNSBBHKSZXKB-VKHMYHEASA-N Asp-Gly Chemical compound OC(=O)C[C@H](N)C(=O)NCC(O)=O JHFNSBBHKSZXKB-VKHMYHEASA-N 0.000 description 1
- OAMLVOVXNKILLQ-BQBZGAKWSA-N Asp-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](N)CC(O)=O OAMLVOVXNKILLQ-BQBZGAKWSA-N 0.000 description 1
- DWBZEJHQQIURML-IMJSIDKUSA-N Asp-Ser Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CO)C(O)=O DWBZEJHQQIURML-IMJSIDKUSA-N 0.000 description 1
- IQTUDDBANZYMAR-UHFFFAOYSA-N Asparaginyl-Methionine Chemical compound CSCCC(C(O)=O)NC(=O)C(N)CC(N)=O IQTUDDBANZYMAR-UHFFFAOYSA-N 0.000 description 1
- VGRHZPNRCLAHQA-UHFFFAOYSA-N Aspartyl-Asparagine Chemical compound OC(=O)CC(N)C(=O)NC(CC(N)=O)C(O)=O VGRHZPNRCLAHQA-UHFFFAOYSA-N 0.000 description 1
- 241000304886 Bacilli Species 0.000 description 1
- 229940044172 CALCIUM FORMATE Drugs 0.000 description 1
- 101700046715 CSTI Proteins 0.000 description 1
- CBOCVOKPQGJKKJ-UHFFFAOYSA-L Calcium formate Chemical compound [Ca+2].[O-]C=O.[O-]C=O CBOCVOKPQGJKKJ-UHFFFAOYSA-L 0.000 description 1
- 229940041514 Candida albicans extract Drugs 0.000 description 1
- 102000005575 Cellulases Human genes 0.000 description 1
- 108010084185 Cellulases Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 101700020566 DEFA4 Proteins 0.000 description 1
- IQFYYKKMVGJFEH-XLPZGREQSA-N DEOXYTHYMIDINE Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 1
- 238000001712 DNA sequencing Methods 0.000 description 1
- 108010067770 Endopeptidase K Proteins 0.000 description 1
- RWLALWYNXFYRGW-UHFFFAOYSA-N Etohexadiol Chemical compound CCCC(O)C(CC)CO RWLALWYNXFYRGW-UHFFFAOYSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 102000000802 Galectin 3 Human genes 0.000 description 1
- 108010001517 Galectin 3 Proteins 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- JEFZIKRIDLHOIF-BYPYZUCNSA-N Gln-Gly Chemical compound NC(=O)CC[C@H](N)C(=O)NCC(O)=O JEFZIKRIDLHOIF-BYPYZUCNSA-N 0.000 description 1
- LSPKYLAFTPBWIL-BYPYZUCNSA-N Glu-Gly Chemical compound OC(=O)CC[C@H](N)C(=O)NCC(O)=O LSPKYLAFTPBWIL-BYPYZUCNSA-N 0.000 description 1
- YBAFDPFAUTYYRW-YUMQZZPRSA-N Glu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](N)CCC(O)=O YBAFDPFAUTYYRW-YUMQZZPRSA-N 0.000 description 1
- 229960002743 Glutamine Drugs 0.000 description 1
- SSHIXEILTLPAQT-UHFFFAOYSA-N Glutaminyl-Aspartate Chemical compound NC(=O)CCC(N)C(=O)NC(CC(O)=O)C(O)=O SSHIXEILTLPAQT-UHFFFAOYSA-N 0.000 description 1
- IKAIKUBBJHFNBZ-LURJTMIESA-N Gly-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)CN IKAIKUBBJHFNBZ-LURJTMIESA-N 0.000 description 1
- BCCRXDTUTZHDEU-VKHMYHEASA-N Gly-Ser Chemical compound NCC(=O)N[C@@H](CO)C(O)=O BCCRXDTUTZHDEU-VKHMYHEASA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 102200001088 HSPB1 S78D Human genes 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 101710006353 IP3R Proteins 0.000 description 1
- 101700035656 ISOTI Proteins 0.000 description 1
- 101700035039 ITI Proteins 0.000 description 1
- 101700052013 ITR2 Proteins 0.000 description 1
- 101700068039 ITRP Proteins 0.000 description 1
- JWBXCSQZLLIOCI-GUBZILKMSA-N Ile-Leu Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@H](C(O)=O)CC(C)C JWBXCSQZLLIOCI-GUBZILKMSA-N 0.000 description 1
- BCXBIONYYJCSDF-CIUDSAMLSA-N Ile-Val Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](C(C)C)C(O)=O BCXBIONYYJCSDF-CIUDSAMLSA-N 0.000 description 1
- 229940060367 Inert Ingredients Drugs 0.000 description 1
- 239000007836 KH2PO4 Substances 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N Kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
- DEFJQIDDEAULHB-IMJSIDKUSA-N L-alanyl-L-alanine Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(O)=O DEFJQIDDEAULHB-IMJSIDKUSA-N 0.000 description 1
- QOOWRKBDDXQRHC-BQBZGAKWSA-N L-lysyl-L-alanine Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN QOOWRKBDDXQRHC-BQBZGAKWSA-N 0.000 description 1
- RNKSNIBMTUYWSH-YFKPBYRVSA-N L-prolylglycine Chemical compound [O-]C(=O)CNC(=O)[C@@H]1CCC[NH2+]1 RNKSNIBMTUYWSH-YFKPBYRVSA-N 0.000 description 1
- 101710019425 LARS2 Proteins 0.000 description 1
- 101700021119 LEUC Proteins 0.000 description 1
- AZLASBBHHSLQDB-GUBZILKMSA-N Leu-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H](N)CC(C)C AZLASBBHHSLQDB-GUBZILKMSA-N 0.000 description 1
- OTXBNHIUIHNGAO-UWVGGRQHSA-N Leu-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(O)=O)CCCCN OTXBNHIUIHNGAO-UWVGGRQHSA-N 0.000 description 1
- VTJUNIYRYIAIHF-IUCAKERBSA-N Leu-Pro Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(O)=O VTJUNIYRYIAIHF-IUCAKERBSA-N 0.000 description 1
- 241000238634 Libellulidae Species 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 241000209082 Lolium Species 0.000 description 1
- 210000004072 Lung Anatomy 0.000 description 1
- 239000006137 Luria-Bertani broth Substances 0.000 description 1
- HGNRJCINZYHNOU-LURJTMIESA-N Lys-Gly Chemical compound NCCCC[C@H](N)C(=O)NCC(O)=O HGNRJCINZYHNOU-LURJTMIESA-N 0.000 description 1
- MYTOTTSMVMWVJN-STQMWFEESA-N Lys-Tyr Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 MYTOTTSMVMWVJN-STQMWFEESA-N 0.000 description 1
- JPNRPAJITHRXRH-UHFFFAOYSA-N Lysyl-Asparagine Chemical compound NCCCCC(N)C(=O)NC(C(O)=O)CC(N)=O JPNRPAJITHRXRH-UHFFFAOYSA-N 0.000 description 1
- IGRMTQMIDNDFAA-UHFFFAOYSA-N Lysyl-Histidine Chemical compound NCCCCC(N)C(=O)NC(C(O)=O)CC1=CN=CN1 IGRMTQMIDNDFAA-UHFFFAOYSA-N 0.000 description 1
- 101700036939 MTI Proteins 0.000 description 1
- 241000288147 Meleagris gallopavo Species 0.000 description 1
- QTZXSYBVOSXBEJ-WDSKDSINSA-N Met-Asp Chemical compound CSCC[C@H](N)C(=O)N[C@H](C(O)=O)CC(O)=O QTZXSYBVOSXBEJ-WDSKDSINSA-N 0.000 description 1
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L MgCl2 Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 1
- 210000004080 Milk Anatomy 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M Monopotassium phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 102000035348 Neutral proteases Human genes 0.000 description 1
- 108091005544 Neutral proteases Proteins 0.000 description 1
- 239000006057 Non-nutritive feed additive Substances 0.000 description 1
- 229920001850 Nucleic acid sequence Polymers 0.000 description 1
- 229920002601 Oligoester Polymers 0.000 description 1
- 229920000272 Oligonucleotide Polymers 0.000 description 1
- 241001319148 Pharmacis Species 0.000 description 1
- JWBLQDDHSDGEGR-DRZSPHRISA-N Phe-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 JWBLQDDHSDGEGR-DRZSPHRISA-N 0.000 description 1
- FSXRLASFHBWESK-HOTGVXAUSA-N Phe-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 FSXRLASFHBWESK-HOTGVXAUSA-N 0.000 description 1
- FELJDCNGZFDUNR-WDSKDSINSA-N Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1 FELJDCNGZFDUNR-WDSKDSINSA-N 0.000 description 1
- JQOHKCDMINQZRV-WDSKDSINSA-N Pro-Asn Chemical compound NC(=O)C[C@@H](C([O-])=O)NC(=O)[C@@H]1CCC[NH2+]1 JQOHKCDMINQZRV-WDSKDSINSA-N 0.000 description 1
- IWIANZLCJVYEFX-RYUDHWBXSA-N Pro-Phe Chemical compound C([C@@H](C(=O)O)NC(=O)[C@H]1NCCC1)C1=CC=CC=C1 IWIANZLCJVYEFX-RYUDHWBXSA-N 0.000 description 1
- AFWBWPCXSWUCLB-WDSKDSINSA-N Pro-Ser Chemical compound OC[C@@H](C([O-])=O)NC(=O)[C@@H]1CCC[NH2+]1 AFWBWPCXSWUCLB-WDSKDSINSA-N 0.000 description 1
- BEPSGCXDIVACBU-UHFFFAOYSA-N Prolyl-Histidine Chemical compound C1CCNC1C(=O)NC(C(=O)O)CC1=CN=CN1 BEPSGCXDIVACBU-UHFFFAOYSA-N 0.000 description 1
- 239000007759 RPMI Media 1640 Substances 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 101710028865 SBT Proteins 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- SSJMZMUVNKEENT-IMJSIDKUSA-N Ser-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H](N)CO SSJMZMUVNKEENT-IMJSIDKUSA-N 0.000 description 1
- UJTZHGHXJKIAOS-WHFBIAKZSA-N Ser-Gln Chemical compound OC[C@H](N)C(=O)N[C@H](C(O)=O)CCC(N)=O UJTZHGHXJKIAOS-WHFBIAKZSA-N 0.000 description 1
- LAFKUZYWNCHOHT-WHFBIAKZSA-N Ser-Glu Chemical compound OC[C@H](N)C(=O)N[C@H](C(O)=O)CCC(O)=O LAFKUZYWNCHOHT-WHFBIAKZSA-N 0.000 description 1
- LDEBVRIURYMKQS-UHFFFAOYSA-N Serinyl-Threonine Chemical compound CC(O)C(C(O)=O)NC(=O)C(N)CO LDEBVRIURYMKQS-UHFFFAOYSA-N 0.000 description 1
- LZLREEUGSYITMX-UHFFFAOYSA-N Serinyl-Tryptophan Chemical compound C1=CC=C2C(CC(NC(=O)C(CO)N)C(O)=O)=CNC2=C1 LZLREEUGSYITMX-UHFFFAOYSA-N 0.000 description 1
- 210000002966 Serum Anatomy 0.000 description 1
- HLBBKKJFGFRGMU-UHFFFAOYSA-M Sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
- 239000004280 Sodium formate Substances 0.000 description 1
- BTURAGWYSMTVOW-UHFFFAOYSA-M Sodium laurate Chemical compound [Na+].CCCCCCCCCCCC([O-])=O BTURAGWYSMTVOW-UHFFFAOYSA-M 0.000 description 1
- 229940082004 Sodium laurate Drugs 0.000 description 1
- 210000001744 T-Lymphocytes Anatomy 0.000 description 1
- 101700062451 TI Proteins 0.000 description 1
- FRPJTGXMTIIFIT-UHFFFAOYSA-N Tetraacetylethylenediamine Chemical compound CC(=O)C(N)(C(C)=O)C(N)(C(C)=O)C(C)=O FRPJTGXMTIIFIT-UHFFFAOYSA-N 0.000 description 1
- BWUHENPAEMNGQJ-ZDLURKLDSA-N Thr-Gln Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(O)=O)CCC(N)=O BWUHENPAEMNGQJ-ZDLURKLDSA-N 0.000 description 1
- DSGIVWSDDRDJIO-ZXXMMSQZSA-N Thr-Thr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O DSGIVWSDDRDJIO-ZXXMMSQZSA-N 0.000 description 1
- YKRQRPFODDJQTC-UHFFFAOYSA-N Threoninyl-Lysine Chemical compound CC(O)C(N)C(=O)NC(C(O)=O)CCCCN YKRQRPFODDJQTC-UHFFFAOYSA-N 0.000 description 1
- YBRHKUNWEYBZGT-UHFFFAOYSA-N Tryptophyl-Threonine Chemical compound C1=CC=C2C(CC(N)C(=O)NC(C(O)C)C(O)=O)=CNC2=C1 YBRHKUNWEYBZGT-UHFFFAOYSA-N 0.000 description 1
- NLKUJNGEGZDXGO-XVKPBYJWSA-N Tyr-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 NLKUJNGEGZDXGO-XVKPBYJWSA-N 0.000 description 1
- HPYDSVWYXXKHRD-VIFPVBQESA-N Tyr-Gly Chemical compound [O-]C(=O)CNC(=O)[C@@H]([NH3+])CC1=CC=C(O)C=C1 HPYDSVWYXXKHRD-VIFPVBQESA-N 0.000 description 1
- MFEVVAXTBZELLL-UHFFFAOYSA-N Tyrosyl-Threonine Chemical compound CC(O)C(C(O)=O)NC(=O)C(N)CC1=CC=C(O)C=C1 MFEVVAXTBZELLL-UHFFFAOYSA-N 0.000 description 1
- 229940035893 Uracil Drugs 0.000 description 1
- 108010064997 VPY tripeptide Proteins 0.000 description 1
- HSRXSKHRSXRCFC-WDSKDSINSA-N Val-Ala Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C)C(O)=O HSRXSKHRSXRCFC-WDSKDSINSA-N 0.000 description 1
- JKHXYJKMNSSFFL-IUCAKERBSA-N Val-Lys Chemical compound CC(C)[C@H](N)C(=O)N[C@H](C(O)=O)CCCCN JKHXYJKMNSSFFL-IUCAKERBSA-N 0.000 description 1
- YSGSDAIMSCVPHG-YUMQZZPRSA-N Val-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@@H](N)C(C)C YSGSDAIMSCVPHG-YUMQZZPRSA-N 0.000 description 1
- GIAZPLMMQOERPN-YUMQZZPRSA-N Val-Pro Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(O)=O GIAZPLMMQOERPN-YUMQZZPRSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 108010056243 alanylalanine Proteins 0.000 description 1
- 108010044940 alanylglutamine Proteins 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000008051 alkyl sulfates Chemical class 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 235000019418 amylase Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 230000003255 anti-acne Effects 0.000 description 1
- 102000004965 antibodies Human genes 0.000 description 1
- 108090001123 antibodies Proteins 0.000 description 1
- 239000002518 antifoaming agent Substances 0.000 description 1
- 108010077245 asparaginyl-proline Proteins 0.000 description 1
- 108010047857 aspartylglycine Proteins 0.000 description 1
- 108010092854 aspartyllysine Proteins 0.000 description 1
- 239000000987 azo dye Substances 0.000 description 1
- 230000001580 bacterial Effects 0.000 description 1
- 230000003796 beauty Effects 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 230000003115 biocidal Effects 0.000 description 1
- 238000004061 bleaching Methods 0.000 description 1
- 239000007844 bleaching agent Substances 0.000 description 1
- 239000001045 blue dye Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 102220404114 c.244C>T Human genes 0.000 description 1
- 235000019255 calcium formate Nutrition 0.000 description 1
- 239000004281 calcium formate Substances 0.000 description 1
- 125000004432 carbon atoms Chemical group C* 0.000 description 1
- 238000005277 cation exchange chromatography Methods 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 229910052570 clay Inorganic materials 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 229960005188 collagen Drugs 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000000551 dentifrice Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 229940028356 diethylene glycol monobutyl ether Drugs 0.000 description 1
- 230000003292 diminished Effects 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000010573 double replacement reaction Methods 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 239000007938 effervescent tablet Substances 0.000 description 1
- 235000014103 egg white Nutrition 0.000 description 1
- 210000000969 egg white Anatomy 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000002708 enhancing Effects 0.000 description 1
- 230000002255 enzymatic Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N ethanolamine Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-M ethyl carbonate Chemical class CCOC([O-])=O CQDGTJPVBWZJAZ-UHFFFAOYSA-M 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000002979 fabric softener Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002068 genetic Effects 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- KGNSGRRALVIRGR-UHFFFAOYSA-N gln-tyr Chemical compound NC(=O)CCC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 KGNSGRRALVIRGR-UHFFFAOYSA-N 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 108010078144 glutaminyl-glycine Proteins 0.000 description 1
- STKYPAFSDFAEPH-LURJTMIESA-N gly-val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)CN STKYPAFSDFAEPH-LURJTMIESA-N 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000002332 glycine derivatives Chemical class 0.000 description 1
- 108010027668 glycyl-alanyl-valine Proteins 0.000 description 1
- 108010079413 glycyl-prolyl-glutamic acid Proteins 0.000 description 1
- 108010082286 glycyl-seryl-alanine Proteins 0.000 description 1
- 108010010147 glycylglutamine Proteins 0.000 description 1
- YMAWOPBAYDPSLA-UHFFFAOYSA-N glycylglycine zwitterion Chemical compound [NH3+]CC(=O)NCC([O-])=O YMAWOPBAYDPSLA-UHFFFAOYSA-N 0.000 description 1
- 108010050848 glycylleucine Proteins 0.000 description 1
- 108010015792 glycyllysine Proteins 0.000 description 1
- 108010087823 glycyltyrosine Proteins 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 108010085325 histidylproline Proteins 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000003752 hydrotrope Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 108010078274 isoleucylvaline Proteins 0.000 description 1
- 229960000318 kanamycin Drugs 0.000 description 1
- 101700020911 lcnA Proteins 0.000 description 1
- 108010083708 leucyl-aspartyl-valine Proteins 0.000 description 1
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 1
- 108010034529 leucyl-lysine Proteins 0.000 description 1
- 108010057821 leucylproline Proteins 0.000 description 1
- 108010012058 leucyltyrosine Proteins 0.000 description 1
- 102000004882 lipase Human genes 0.000 description 1
- 108090001060 lipase Proteins 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 238000005567 liquid scintillation counting Methods 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 230000003020 moisturizing Effects 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative Effects 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- 230000000849 parathyroid Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920005646 polycarboxylate Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 238000001742 protein purification Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000002829 reduced Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 102220246481 rs147782267 Human genes 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000019254 sodium formate Nutrition 0.000 description 1
- VQOIVBPFDDLTSX-UHFFFAOYSA-M sodium;3-dodecylbenzenesulfonate Chemical class [Na+].CCCCCCCCCCCCC1=CC=CC(S([O-])(=O)=O)=C1 VQOIVBPFDDLTSX-UHFFFAOYSA-M 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 230000003381 solubilizing Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000020382 suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Effects 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- FAGUFWYHJQFNRV-UHFFFAOYSA-N tetraethylenepentamine Chemical class NCCNCCNCCNCCN FAGUFWYHJQFNRV-UHFFFAOYSA-N 0.000 description 1
- 108010061238 threonyl-glycine Proteins 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 239000000606 toothpaste Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
- 108010020532 tyrosyl-proline Proteins 0.000 description 1
- 108010003137 tyrosyltyrosine Proteins 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 125000002987 valine group Chemical group [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
- 239000010457 zeolite Substances 0.000 description 1
- 239000002888 zwitterionic surfactant Substances 0.000 description 1
- GUBGYTABKSRVRQ-ASMJPISFSA-N α-maltose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-ASMJPISFSA-N 0.000 description 1
- DXJZITDUDUPINW-UHFFFAOYSA-N γ-glutamyl-Asparagine Chemical compound NC(=O)CCC(N)C(=O)NC(CC(N)=O)C(O)=O DXJZITDUDUPINW-UHFFFAOYSA-N 0.000 description 1
- UKKNTTCNGZLJEX-UHFFFAOYSA-N γ-glutamyl-Serine Chemical compound NC(=O)CCC(N)C(=O)NC(CO)C(O)=O UKKNTTCNGZLJEX-UHFFFAOYSA-N 0.000 description 1
Abstract
The present invention relates to variants of serine proteases having decreased immunogenicity relative to their corresponding wild-type proteases. More particularly, the present invention relates to variants having a modified amino acid sequence of a wild-type amino acid sequence, wherein the modified amino acid sequence comprises a substitution of one or more specifically identified positions corresponding to subtilisin BPN'. The invention further relates to mutant genes encoding such variants and cleaning and personal care compositions comprising such variants.
Description
SERINE PROTEASE VARIANTS THAT HAVE AMINO ACID SUBSTITUTIONS
FIELD OF THE INVENTION
The present invention relates to serine protease variants and compositions comprising the variants and having decreased immunogenicity in relation to their corresponding wild-type serine proteases.
BACKGROUND OF THE INVENTION
Enzymes are the largest class of proteins that occur naturally. One class of enzyme includes proteases that catalyze the hydrolysis of other proteins. This ability to hydrolyze proteins has been exploited by incorporating proteases that occur naturally and proteases manipulated by genetic engineering in cleaning compositions, particularly those pertinent to laundry applications. In cleaning techniques, the most widely used of these proteases are serine proteases. Most of these serine proteases are produced by bacterial organisms while some are produced by other organisms, such as fungi. See Siezen, Roland J. et al., "Homology Modeling and Protein Engineering Strategy of Subtilases, the Family of Subtilisin-Like Serine Proteases", Protein Engineering, Vol. 4, No. 7, pp. 719-737 (1991). Unfortunately, the effectiveness of wild-type proteases in their natural environment often does not translate to the environment of the unnatural cleaning composition. Specifically, the characteristics of the protease such as, for example, thermal stability, pH stability, oxidative stability and substrate specificity are not necessarily optimized by utilizing the enzyme outside the natural environment. Various methods have been employed to alter the wild-type amino acid sequence of serine proteases with the goal of increasing the efficacy of the protease in the wash environment that is not natural. These approaches include the genetic redesign of proteases to increase thermal stability and to improve stability to oxidation under very diverse conditions. However, because such genetically engineered proteases are foreign to mammals, they are potential antigens. As antigens, these proteases produce immunological and allergic responses (collectively described here as immunological responses) in mammals. In fact, sensitization to serine proteases has been observed in environments where humans are regularly exposed to proteases. Such environments include manufacturing facilities, where employees are exposed to proteases through vehicles such as uncontrolled dust or aerosolization. Aerosolization can occur by introducing the protease into the lung, which is the route of exposure of the protease that causes the most dangerous response. Protease sensitization can also occur in the market, where the repeated use of products containing proteases by consumers can cause an allergic reaction. In addition, although genetic engineering has been prominent in the continuing search for more highly effective proteases to be used in laundry applications, genetically engineered proteases have been used to a minimum in personal care compositions and light duty detergents. A major reason for the absence of genetically engineered proteases in products such as, for example, soaps, gels, body washes and shampoos is due to the aforementioned problem of human sensitization leading to undesirable immune responses. Therefore, it would be highly advantageous to provide a personal care composition that would provide the cleaning properties of the proteases manipulated by genetic engineering with minimal provocation of immune responses. One method that leads to the alleviation of the immunological activity of a protease is through the redesign of one or more epitopes of the protease. Epitopes are those regions of amino acids in an antigen that induce an immune response through the binding of antibodies or the presentation of processed antigens to T cells through a major histocompatibility complex protein (MHC). Changes in epitopes can affect its efficiency as an antigen. See Walsh, B. J. and M.E.H. Howden, "A Method for the Detection of IgE Binding Sequences of Allergens Based on a Modification of Epitope Mapping", Journal of Immunological Methods, Vol. 121, pp. 275-280 (1989). The inventors of the present invention have discovered that those serine proteases commonly known as subtilisins, including subtilisin BPN ', have a prominent epitope region at positions 70-84 of amino acids corresponding to BPN'. The inventors of the present invention have genetically redesigned here such subtilisins to remedy the immunogenic properties attributed to this epitope region. In doing so, the inventors of the present invention have discovered subtilisins that induce a diminished immune response but maintain their activity as an efficient cleaning protease. Accordingly, the proteases of the present invention are suitable for use in various types of compositions including, but not limited to laundry, dishwashing, hard surfaces, skin care, hair care, beauty care, oral compositions and compositions for contact lenses.
BRIEF DESCRIPTION OF THE INVENTION
The present invention relates to serine protease variants having decreased immunogenicity in relation to their corresponding wild-type proteases. Most particularly, the present invention relates to variants having a modified amino acid sequence of a wild-type amino acid sequence, wherein the modified amino acid sequence comprises a substitution of one or more positions 70-84 corresponding to subtilisin BPN ' . The invention also relates to mutant genes encoding the variants and cleansing and personal care compositions containing said variants.
DETAILED DESCRIPTION OF THE INVENTION
The essential components of the present invention are described below. Also included are non-limiting descriptions of various optional and preferred components useful in the embodiments of the present invention. The present invention may comprise, consist of or consist essentially of any of the required or optional components and / or limitations described herein. All percentages and ratios are calculated by weight unless otherwise indicated. All percentages are calculated based on the total composition unless otherwise indicated. All levels of component or composition are in reference to the active level of that component or composition, and are exclusive of impurity, for example, residual solvents or by-products, which may be present in commercially available sources. All documents referred to herein, including all patents, patent applications and printed publications, are hereby incorporated by reference in their entirety. As used herein, abbreviations will be used to describe amino acids. Table 1 provides a list of abbreviations used in the present invention.
TABLE 1
Definitions As used herein, the term "mutation" refers to alterations in gene sequences and amino acid sequences produced by those gene sequences. The mutations can be deletions, substitutions or additions of amino acid residues to the sequence of wild-type proteins. As used herein, the term "wild type" refers to a protein, specifically a protease, produced by organisms that have not undergone mutation. As used herein, the term "variant" means a protein, specifically a protease, having an amino acid sequence that differs from that of the wild-type protease. As referred to herein, although the variants of the present invention are not limited to those of the subtilisins BPN ', the numbering of all the amino acids is with reference to the amino acid sequence for the subtilisin BPN' which is represented by SEQ ID NO. : 1. The amino acid sequence for subtilisin BPN 'is further described in Wells, JA, E. Ferrari, DJ Henner, D.A. Estell, and E.Y. Chen, Nucleic Acids Research, Vol. II, 7911-7925 (1983), incorporated herein by reference.
Variants of the present invention The inventors of the present invention have discovered an epitope region in serine protease corresponding to positions 70-84 of subtilisin BPN '. The inventors of the present invention have also discovered that one or more amino acid substitutions in the amino acid sequence of a wild type serine protease provides variants that induce a decreased allergenic response and / or decreased immune response relative to the protease type resin. corresponding wild. As used herein, a variant can be designated by reference to the substituted amino acid positions characterizing the variant. Substitutions are indicated herein by providing the wild-type amino acid residue, followed by the position number, and followed by the substituted amino acid residue to be substituted. Where the substituted amino acid residue can be any natural amino acid allowed in that particular position, the symbol "*" is given. Multiple substitutions that comprise a variant are separated by the "+" symbol. To illustrate this, a substitution of glycine for valine at position 70 is designated Gly70Val or G70V. An example of a variant having a substitution in both positions 70 and 72 can be designated Gly70Val + Val72Ala or G70V + V72A. The variants of the present invention are variants of serine protease. As used herein, the term "serine protease" means a protease having at least 50%, and preferably 80%, of amino acid sequence identity with the sequence for one or more of a serine protease similar to subtilisin. A discussion related to serine proteases similar to subtilisin and its homologies can be found in Siezen et al., "Homology Modeling and Protein Engineering Strategy of Subtilisases, the Family of Subtilisin-Like Serine Proteases", Protein Engineering, Vol. 4, No. 7, pp. 719-737 (1991). Preferred serine proteases for mutation include subtilisin BPN ', subtilisin Carlsberg, subtilisin DY, subtilisin 309, proteinase K and termitase. The serine protease that is most preferred for mutation is subtilisin BPN '. The variants of the present invention are variants of serine proteases having a modified amino acid sequence of a wild-type amino acid sequence, wherein the modified amino acid sequence comprises a substitution of one or more of positions 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83 and 84 (70-84) corresponding to BPN '. Most preferably, the modified amino acid sequence comprises a substitution of two or more of these positions. Substitutions at these positions are made by replacing the wild-type amino acid residue with another natural amino acid residue such as that given in Table 1. Very specifically, wherein the variant has a modified amino acid sequence of an amino acid sequence wild type 0
comprising a substitution at a position corresponding to positions 70-84 of BPN ': a) When substitution occurs at position 70, the substituent amino acid is selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Glu , Phe, His, lie, Lys, Leu, Met, Pro, Gln, Ser, Thr, Trp, Tyr and Val; b) When the substitution occurs at position 71, the amino acid substituent is selected from the group consisting of Ala, Arg, Asn, Cys, Gly, Phe, His, Lie, Lys, Leu, Met, Pro, Gln, Ser, Trp , Tyr and Val; c) When the substitution occurs at position 72, the substituent amino acid is selected from the group consisting of Ala, Arg, Asn, Asp, Cys,
Glu, Gly, Phe, His, Lie, Lys, Leu, Met, Pro, Gln, Ser, Thr, Trp, Tyr and Val; d) When the substitution occurs at position 73, the amino acid substituent is selected from the group consisting of Arg, Asn, Asp, Cys, Glu, Gly, Phe, His, Lie, Lys, Met, Pro, Ser, Thr, Trp , Tyr and Val; e) When the substitution occurs at position 74, the amino acid substituent is selected from the group consisting of Arg, Asn, Asp, Cys, Glu, Gly, Phe, His, Lie, Lys, Leu, Met, Gln, Ser, Thr , Trp, Tyr and Val; f) When the substitution occurs at position 75, the amino acid substituent is selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Glu, Gly, Phe, His, Lie, Lys, Met, Gln, Ser, Thr , Trp, Tyr and Val; g) When the substitution occurs at position 76, the substituent amino acid is selected from the group consisting of Ala, Arg, Cys, Lie, Leu, Met, Gln, Ser, Thr, Trp, Tyr and Val;
h) When the substitution occurs at position 77, the amino acid substituent is selected from the group consisting of Ala, Arg, Cys, Glu, Gly, Phe, His, Lie, Lys, Leu, Met, Pro, Gln, Ser, Thr , Trp, Tyr and Val; i) When the substitution occurs at position 78, the amino acid substituent is selected from the group consisting of Ala, Arg, Asn, Cys, Glu, Gly, Phe, His, Lie, Lys, Leu, Met, Pro, Gln, Thr , Trp, Tyr and Val; j) When the substitution occurs at position 79, the amino acid substituent is selected from the group consisting of Ala, Arg, Asn, Cys, Gly, Phe, His, Lys, Leu, Met, Pro, Gln, Ser, Thr, Trp , Tyr and Val; k) When the substitution occurs at position 80, the amino acid substituent is selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Glu, Phe, His, Lie, Lys, Leu, Met, Pro, Gln, Ser , Thr, Trp, Tyr and Val; I) When the substitution occurs at position 81, the amino acid substituent is selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Glu, Gly, Phe, His, He, Lys, Leu, Met, Pro, Gln , Ser, Thr, Trp and Tyr; m) When substitution occurs at position 82, the amino acid substituent is selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Glu, Gly, Phe, His, Lie, Lys, Met, Pro, Gln, Ser , Thr, Trp, Tyr and Val; n) When the substitution occurs at position 83, the amino acid substituent is selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Glu, Phe, His, Lie, Lys, Leu, Met, Pro, Gln, Ser , Thr, Trp, Tyr and Val; i) When the substitution occurs at position 84, the amino acid substituent is selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Glu, Gly, Phe, His, lie, Lys, Leu, Met, Pro, Gln , Ser, Thr, Trp and Tyr. Wherein the variant has a modified amino acid sequence of a wild-type amino acid sequence comprising a substitution at two or more positions corresponding to positions 70-84 of BPN ': a) When a substitution occurs at position 70, the amino acid substituent is selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Gln, Glu, Phe, His, Lie, Lys, Leu, Met, Pro, Ser, Thr, Trp, Tyr and Val; b) When a substitution occurs at position 71, the amino acid substituent is selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, Phe, His, lie, Lys, Leu, Met, Pro , Ser, Trp, Tyr and Val; c) When a substitution occurs at position 72, the amino acid substituent is selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, Phe, His, lie, Lys, Leu, Met, Pro , Ser, Thr, Trp and Tyr; d) When a substitution occurs at position 73, the amino acid substituent is selected from the group consisting of Arg, Asn, Asp, Cys, Gln, Glu, Gly, Phe, Hís, Lie, Lys, Leu, Met, Pro, Ser , Thr, Trp, Tyr and Val;
e) When a substitution occurs at position 74, the amino acid substituent is selected from the group consisting of Arg, Asn, Asp, Cys, Gln, Glu, Gly, Phe, His, lie, Lys, Leu, Met, Pro, Ser , Thr, Trp, Tyr and Val; f) When a substitution occurs at position 75, the amino acid substituent is selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, Phe, His, He, Lys, Met, Pro, Ser , Thr, Trp, Tyr and Val; g) When a substitution occurs at position 76, the amino acid substituent is selected from the group consisting of Ala, Arg, Asp, Cys, Gln, Glu, Gly, Phe, His, lie, Lys, Leu, Met, Pro, Ser , Thr, Trp, Tyr and Val; h) When a substitution occurs at position 77, the amino acid substituent is selected from the group consisting of Ala, Arg, Asp, Cys, Gln, Glu, Gly, Phe, His, lie, Lys, Leu, Met, Pro, Ser , Thr, Trp, Tyr and Val; i) When a substitution occurs at position 78, the amino acid substituent is selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, Phe, His, lie, Lys, Leu, Met, Pro , Thr, Trp, Tyr and Val; j) When a substitution occurs at position 79, the substitution amino acid is selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, Phe, His, Lys, Leu, Met, Pro, Ser , Thr, Trp, Tyr and Val; k) When a substitution occurs at position 80, the amino acid substituent is selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Gln, Glu, Phe, hiis, lie, Lys, Leu, Met, Pro, Ser , Thr, Trp, Tyr and
Val; I) When a substitution occurs at position 81, the amino acid substituent is selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Gln.Glu, Gly, Phe, His, lie, Lys, Leu, Met, Pro , Ser, Thr, Trp and Tyr; m) When a substitution occurs at position 82, the substituent amino acid is selected from the group consisting of Ala, Arg,
Asn, Asp, Cys, Gln, Glu, Gly, Phe, His, Lie, Lys, Met, Pro, Ser, Thr, Trp, Tyr and
Val; n) When a substitution occurs at position 83, the amino acid substituent is selected from the group consisting of Ala, Arg,
Asn, Asp, Cys, Gln, Glu, Phe, His, He, Lys, Leu, Met, Pro, Ser, Thr, Trp, Tyr and
Val; and o) When a substitution occurs at position 84, the substituent amino acid is selected from the group consisting of Ala, Arg,
Asn, Asp, Cys, Gln, Glu, Gly, Phe, His, He, Lys, Leu, Met, Pro, Ser, Thr, Trp and
Tyr; where the variant is not Asn76Asp + Asn77Asp; Asn76Asp + He76Glu; or
Asn76Asp + Ser78Asp. Most preferably still, the variants of the present invention comprise a deletion of one or more of the positions 73 74, 75, 76, 77,
78, 79, 80, 81, 82, 83 (73-83), most preferably still one or more than 75, 76,
77, 78, 79, 80, 81, 82 (75-82).
The following tables 2-7 illustrate preferred non-limiting variants of the present invention. With respect to these tables, when describing the specific substitutions, first the wild-type amino acid residue is given, second the corresponding position number is given and in the third place the amino acid substituent is given. Tables 3-7 delineate preferred variants having two or more substitutions. To illustrate this, the first example in Table 3 indicates "VAL 81 THR LEU 82 PHE". This example illustrates the variant Val81Thr + Leu82Phe. Using a similar notation, tables 8-13 illustrate even more preferred varieties of the present invention.
TABLE 2 Variants of a single substitution GLY 83 VAL LEU 82 PHE LEU 82 HJ5 LEU 82 T? R LEU 82 WING VAL 81 THR VAL 81 WING GLY 80 VAL IUE 79 LEU ILE 79 MET 1LE 79 THR ILE 79 VAL ILE 79 WING 78 ASN BE 78 TUR BE 78 ARG BE 78 GLN BE 78 HIS BE 78 LYS 10 BE 78 TYR BE 78 WING A &N 77 WING ASN W ALA
LEU 75 iLE LEU 75 MET LEU 75 VAL LEU 75 ALA ALA 74 VAL ALA 73 VAL VAL 72 ALA 15 THR 71 ALA GLY 70 VAL TABLE 3 Variants of double replacement VAL 81 THR LEU 82 PHE VAL SI TUR LEU §2 HIS VAL 81 THR LEU 82 TYR ULE 79 LEU LEU 82 PHE ELE 79 LEU LEU $ 2 H1S 20? LE 79 LEU LEE 82 TYR iLE 79 MET LEU 2 PHE BLE 7 LEV LEE 82 HIS ILE 79 MET LEU 82 T? R ILE 79 THR LEU 82 PHE ILE 79 THR LEU 82 HIS ELE 79 THR LEU 82 TYR ILE 79 VAL LEU 82 PHE 1LE 79 VAL LEU 82 HIS ILE 79 VAL LEU $ 2 TYR AXLE 79 LEU VAL If THR ILE 79 MET VAL 81 THR ILE 79 THR VAL 81 THR ILE 79 VAL VAL SI THR SER 78 ASN LEU 82 PHE SER 78 ASN LEU 82 HIS BE 78 ASN LEU 82 TYR BE 78 THR LEU 82 PHE SER 78 THR LEU 82 H1S SER. 78 THR LEU 82 TYR SER 78 ARG LEU 82 PHE SER 78 ARG LEU 82 H1S SER 78 ARG LEU 82 TYR SER 78 ASP LEU 82 PHE SER 78 ASP LEU 82 HIS SER 78 ASP LEU 82 TYR SER 78 GLN LEU 82 PHE SER 78 GLN LEU 82 HIS BE 78 GLN LEU 82 TYR BE 78 HIS LEU 82 PHE BE 78 HIS LEU 82 HIS BE 78 H1S LEU 82 TYR
BE 78 LYS LEU 82 PHE BE 78 LYS LEU 82 HIS BE 78 LYS LEU 82 T? R BE 78 TYR LEU 82 PHE BE 78 TYR LEU 82 HIS BE 78 TYR LEU 82 TYR BE 78 ASN VAL 81 THR SER 78 THR VAL 81 THR SER 78 ARG VAL 81 THR SER 78 ASP VAL 8! THR SER 78 GLN VAL 81 THR SER 78 HIS VAL 81 THR
SER 78 LYS VAL 81 THR SER 78 TY VAL 81 THR SER 78 ASN ILE 79 LEU SER 78 ASN ILE 79 MET SER 78 ASN ILE 79 THR SER. 78 ASN ILE 79 VAL SER 78 THR ILE 79 LEU SER 78 THR 1LE 79 MET SER 78 THR ILE 79 THR SER 78 THR ILE 79 VAL SER 78 ARG ILE 79 LEU SER 78 ARG? LE 79 MET SER 78 ARG ILE 7 THR
SER 78 ARG ILE 79 VAL SER 78 SP ILE 79 LEU SER 78 ASP AXIS 79 MET SER 78 ASP ILE 79 THR SER 78 ASP ILE 79 VAL SER 78 GLN ILE 79 LEU SER 78 GLN ILE 79 MET SER 78 GLN ILE 79 THR SER 78 GLN ILE 79 VAL SER 78 HiS ILE - > 9 LEU SER 78 HIS ILE 79 MET SER 78 HIS ILE 79 THR SER 78 HIS ILE 79 VAL SER 78 LYS ILE 79 LEU SER 78 LYS ILE 79 MET SER 78 LYS ILE 79 THR SER 78 LYS ILE 79 VAL SER 78 TYR ÍLE 79 LEU SER 78 TYR ILE 79 MET SER 78 TYR ILE 79 THR SER 78 TYR ILE 79 VAL ASN 76 HIS LEU 82 PHE ASN 76 HIS LEU 82 HIS ASN 76 HIS LEU 82 TYR ASN 76 HIS VAL 81 THR ASN 76 HIS ILE 79 LEU ASN 76 HIS ILE 79 MET ASN 76 H? S ILE 79 THR ASN 76 HiS ILE 79 VAL ASN 76 HIS SER 78 ASN
ASN 76 HIS BE 78 THR ASN 76 HIS BE 78 ARG ASN 76 HIS BE 78 ASP ASN 76 HIS BE 78 GLN ASN 76 HIS BE 78 HIS ASN 76 HIS BE 78 LYS ASN 76 HIS BE 78 T? R LEU 75 ILE LEU 82 PHE LEU 75 1LE LEU 82 HIS LEU 75 ILE LEU 82 TYR LEU 75 MET LEU 82 PHE LEU 75 MET LEU 82 HIS
LEU 75 MET LEU 82 TYR LEU 75 VAL LEU 82 PHE LEU 75 VAL LEU 82 HIS LEU 75 VAL LEU 82 TYR LEU 75 ILE VAL 81 THR LEU 75 MET VAL 81 THR LEU 75 VAL VAL 81 THR LEU 75 ILE ILE 79 LEU LEU 75 ILE ILE 79 MET LEU 75? LE ILE 79 THR LEU 75 ILE ILE 79 VAL LEU 75 MET ILE 79 LEU LEU 75 MET ILE 79 MET
LEU 75 METILE 79 THR LEU 75 MET ILE 79 VAL LEU 75 VAL ILE 79 LEU LEU 75 VAL ILE 79 MET LEU 75 VAL ILE 79 THR LEU 75 VAL ILE 79 VAL LEU 75 ILE SER 78 ASN LEU 75 ILE SER 78 THR LEU 75 ILE BE 78 ARG LEU 75 ILE BE 78 ASP LEU 75 ILE BE 78 GLN LEU 75 ILE BE 78 H1S LEU 75 ILE BE 78 LYS LEU 75 I WILL BE 78 TYR LEU 75 MET I WILL BE 78 ASN LEU 75 MET BE 78 THR LEU 75 MET BE 78 ARG LEU 75 MET BE 78 ASP LEU 75 MET BE 78 GLN LEU 75 MET BE 78 HIS LEU 75 MET BE 78 LYS LEU 75 MET BE 78 TYR LEU 75 VAL BE 78 ASN LEU 75 VAL BE 78 THR LEU 75 VAL SER 78 ARG LEU 75 VAL SER 78 ASP LEU 75 VAL SER 78 GLN LEU 75 VAL SER 78 HIS LEU 75 VAL SER 78 LYS LEU 75 VAL SER 78 TYR LEU 75 ÍLE ASN 76 HIS LEU 75 MET ASN 76 HIS
LEU 75 VAL ASN 76 H1S TABLE 4 Triple substitution variants ÍLE 79 LEU VAL 81 THR LEU 82 PHE ILE 79 LEU VAL 81 THR LEU 82 HIS ILE 79 LEU VAL 81 THR LEU 82 TYR ILE 79 MET VAL 81 TH LEU 82 PHE ÍLE 79 MET VAL 81 THR LEU 82 HIS LE 79 MET VAL 81 THR LEU 82 TYR
ILE 79 THR VAL 81 THR LEU 82 PHE ILE 79 THR VAL 81 THR LEU 82 H1S ILE 79 THR VAL 8! THR LEU 82 TYR ILE 79 VAL VAL 81 THR LEU 82 PHE 1LE 79 VAL VAL 81 THR LEU 82 HIS HE 79 VAL VAL 81 THR LEU 82 TYR SER 78 ASN VAL 81 THR LEU 82 PHE SER 78 ASN VAL 81 THR LEU 82 HIS SER 78 ASN VAL 81 THR LEU 82 TYR SER 78 THR VAL 81 THR LEU 82 PHE SER 78 THR VAL 81 TH LEU 82 HIS SER 78 THR VAL 81 THR LEU 82 TYR
SER 78 ARG VAL 81 THR LEU 82 PHE SER 78 ARG VAL 81 THR LEU 82 HIS SER 78 ARG VAL 81 THR LEU 82 TYR SER 78 ASP VAL 81 THR LEU 82 PHE SER 78 ASP VAL 81 THR LEU 82 HIS SER 78 ASP VAL 81 THR LEU 82 TYR SER 78 GLN VAL 81 TH LEU 82 PHE SER 78 GLN VAL 81 THR LEU 82 HIS SER 78 GLN VAL 81 THR LEU 82 TYR SER 78 HIS VAL 81 THR LEU 82 PHE SER 78 HIS VAL 81 THR LEU 82 HIS SER 78 HIS VAL 81 THR LEU 82 TYR SER 78 LYS VAL 81 THR LEU 82 PHE SER 78 LYS VAL 81 THR LEU 82 H1S SER 78 LYS VAL 81 THR LEU 82 T? R SER 78 TYR VAL 83 THR LEU 82 PHE SER 78 TYR VAL 81 THR LEU 82 HIS SER 78 TYR VAL 81 THR LEU 82 TYR SER 78 ASN [LE 79 LEU LEE 82 PHE SER 78 ASN ILE 79 LEU LEU 82 HIS SER 78 ASN ILE 79 LEU LEU 82 T? R SER 78 ASN ILE 79 MET LEU 82 PHE SER 78 ASN ILE 79 MET LEU 82 HIS SER 78 ASN ILE 79 MET LEU 82 TYR SER 78 ASN ILE 79 THR LEU 82 PHE SER 78 ASN ILE 79 THR LEU 82 HIS BE 78 ASN ILE 79 THR LEU 82 TYR SER 78 ASN ILE 79 VAL LEU 82 PHE SER 78 ASN LE 79 VAL LEU 82 HIS SER 78 AS N ILE 79 VAL LEU 82 TYR SER 78 THR ILE 79 LEU LEU 82 PHE SER 78 THR ÍLE 79 LEU LEU 82 HIS SER 78 THR ILE 79 LEU LEU 82 TYR
SER 78 THR ILE 79 MET LEU 82 PHE SER 78 THR ILE 79 MET LEU 82 HIS SER 78 THR ILE 79 MET LEU 82 TYR SER 78 THR ILE 79 THR LEU 82 PHE SER 78 THR ILE 79 THR LEU 82 HIS SER 78 THR ÍLE 79 THR LEU 82 T? R SER 78 THR? LE 79 VAL LEU 82 PHE SER 78 THR ILE 79 VAL LEU 82 HIS SER 78 THR 1LE 79 VAL LEU 82 TYR SER 78 ARG ILE 79 LEU LEU 82 PHE SER 78 ARG ILE 79 LEU LEU 82 HIS BE 78 ARG ILE 79 LEU LEU 82 TYR
SER 78 ARG ILE 79 MET LEU 82 PHE SER 78 ARG ILE 79 MET LEU 82 HIS SER 78 ARG ÍLE 79 MET LEU 82 TYR SER 78 ARG ILE 79 THR LEU 82 PHE SER 78 ARG ILE 79 THR LEU 82 HIS SER 78 ARG ILE 79 THR LEU 82 TYR SER 78 ARG ILE 79 VAL LEU 82 PHE SER 78 ARG 1LE 79 VAL LEU 82 HIS BE 78 ARG ÍLE 79 VAL LEU 82 TYR BE 78 ASP ÍLE 79 LEU LEU 82 PHE SER 78 ASP ILE 79 LEU LEU 82 HIS BE 78 ASP ILE 79 LEU LEU 82 TYR BE 78 ASP ILE 79 MET LEU 82 PHE
BE 78 ASP ILE 79 MET LEU 82 HIS BE 78 ASP ILE 79 MET LEU 82 TYR SER 78 ASPEL 79 THR LEU 82 PHE SER 78 ASP iLE 79 THR LEU 82 HIS SER 78 ASP ILE 79 THR LEU 82 TYR SER 78 ASP ILE 79 VAL LEU 82 PHE SER 78 ASP ÍLE 79 VAL LEU 82 HIS SER 78 ASP ILE 79 VAL LEU 82 TYR 2
SER 78 GLN 1LE "9 LEU LEU 82 PHE SER 78 GLN LE 79 LEU S2 HtS SER 78 GLN ILE" 9 LEU LEU 82 TYR SER 78 GLN 1LE 79 MET LEU $ 2 PHE SER 78 GLN ÍLE 79 MET LEU 82 HIS SER 78 GLN ÍLE 79 MET LEU 82 TYR SER 78 GLN ILE 79 THR LEU 82 PHE SER 78 GLN? LE 79 THR LEU 82 HiS SER 78 GLN ILE 79 THR LEU 82 TYR SER 78 GLN ILE 79 VAL LEU 82 PHE SER 78 GLN ÍLE 79 VAL LEU 82 H1S SER 78 GLN ILE 79 VAL LEU 82 TYR SER 78 HIS 1LE 79 LEU LEU 82 PHE SER 78 HIS ILE 79 LEU LEU 82 H1S SER 78 HIS ÍLE 79 LEU LEU 12 TYR SER 78 HIS iLE 79 MET LEU 82 PHE SER 78 HiS? LE 79 MET LEU 82 HIS BE 78 HIS 1LE 79 MET LEU $ 2 TYR BE 78 HIS ILE 79 THR LEU 82 PHE BE 78 HIS ILE 79 TUR LEU 82 HIS BE 1% HIS ILE 79 THR LEU 82 TYR BE 78 HtS ÍLE 79 VAL LEU 82 PHE
BE 78 HIS ILE 79 VAL LEU 82 HJS BE 78 HIS? LE 79 VAL LEU 82 TYR BE 78 LYS? LE 79 LEU LEU 82 PHE SER 78 LYS ILE 79 LEU LEU 82 HIS BE 78 LYS? LE 79 LEU LEU 82 TYR SER 78 LYSELE 79 MET LEE 82 PHE SER 78 LYS ILE 79 MET LEU 82 H1S SER 78 LYS ILE 79 MET LEU 82 TYR SER 78 LYS ILE 79 THR LEU 82 PHE SER 78 LYS 1LE 79 THR LEU 82 HIS BE 7S LYS? LE 79 THR LEU 82 TYR SER 78 LYS ILE 79 VAL LEU 82 PHE
SER 78 LYS ILE 79 VAL LEU 82 HiS SER 78 LYS 1LE 79 VAL LEU 82 TYR SER 78 TYR ÍLE 79 LEU LEU 82 PHE SER 78 TYR ILE 79 LEU LEU 82 HiS SER 78 TYR? LE 79 LEU LEU 82 TYR SER n TYR LE 79 MET LEU 82 PHE BE 78 T? RILE 79 MET LEU 82 HIS SER 7 »TYR JE 79 MET LEU 82 TYR SER 71 TYR DLE 79 THR LEU 82 PHE SER 78 TYR? LE 79 THR LEU 82 HIS SER 78 TYR 1LE 79 THR LEU 82 TYR SER 78 TYR ILE 79 VAL LEU 82 PHE SER 78 TYR HE 79 VAL LEU 82 HIS
SER 78 TY ILE 79 VAL LEU 8? TYR SER 78 ASN? LE 79 LEU VAL 81 THR SER 78 ASN ILE 79 MET VAL 81 THR SER 78 ASN ILE 79 THR VAL 81 THR SER 78 ASN ÍLE 79 VAL VAL 81 THR SER 78 THR ILE 79 LEU VAL 81 THR SER 78 THR ÍLE 79 MET VAL 81 THR SER 78 THR ÍLE 79 THR VAL 81 THR SER 78 THR ILE 79 VAL VAL 81 THR SER 78 ARG ILE 79 LEU VAL 81 THR SER ^ 8 ARG ILE 79 MET VAL 81 THR SER 78 ARG ÍLE 79 THR VAL 8! THR SER 78 ARG [LE 79 VAL VAL 81 THR SER 78 ASP ILE 79 LEU VAL 81 THR SER 78 ASP ILE 79 MET VAL 81 THR SER 78 ASPEL 79 THR VAL 1 THR SER 78 ASP ILE 79 VAL VAL 81 THR SER 78 GLN ILE 79 LEU VAL 81 THR SER 78 GLN ILE 79 MET VAL 81 THR SER 78 GLN ILE 79 THR VAL 81 THR SER 78 GLN ILE 79 VAL VAL 81 THR SER 78 HIS ILE 79 LEU VAL 81 THR SER 78 HIS LE 79 MET VAL 81 THR SER 78 HIS ILE 79 THR VAL 81 THR SER 78 HIS ÍLE 79 VAL VAL 81 THR SER 78 LYS ILE 79 LEU VAL 81 THR SER 78 LYS LE 79 MET VAL 81 THR SER 78 LYS LE 79 THR VAL 81 TUR SER 78 LYS ILE 79 VAL VAL 81 THR SER 78 TYR ILE 79 LEU VAL 81 THR SER 78 TYR LE 79 MET VAL 81 THR
SER 78 TYR ILE 7 THR VAL 81 THR SER 78 TYR LE 79 VAL VAL 81 THR ASN 76 HIS VAL 81 THR LEU 82 PHE ASN 76 HIS VAL 81 THR LEU 82 HIS ASN 76 HIS VAL 81 THR LEU 82 TYR ASN 76 HIS ILE 79 LEU LEU 82 PHE ASN 76 HIS ILE 79 LEU LEU 82 HIS ASN 76 HIS ILE 79 LEU LEU 82 T? R ASN 76 H? S ILE 79 MET LEU 82 PHE ASN 76 HIS ILE 79 MET LEU 82 H? S ASN 76 HIS ILE 79 MET LEU 82 TYR ASN 76 HIS LE 79 THR LEU 82 PHE
ASN 76 HIS LE 79 THR LEU 82 HIS ASN 76 HIS ILE 79 THR LEU 82 TYR ASN 76 HIS ILE 79 VAL LEU 82 PHE ASN 76 HIS ELE 79 VAL LEU 82 H? S ASN 76 HIS LE 79 VAL LEU 82 TYR ASN 76 HIS ILE 79 LEU VAL 81 THR ASN 76 HIS ILE 79 MET VAL 81 THR ASN 76 HIS ILE 79 THR VAL 81 THR ASN 76 HIS? LE 79 VAL VAL 81 THR ASN 76 H3S SER 78 ASN LEU 82 PHE ASN 76 HIS SER 78 ASN LEU 82 HIS ASN 76 HIS BE 78 ASN LEU 82 TYR ASN 76 HIS BE 78 THR LEU 82 PHE
ASN 76 H? S BE 78 TH LEU 82 HIS ASN 76 HIS BE 78 THR LEU 82 TYR ASN 76 HIS BE 78 ARG LEU 82 PHE ASN 76 HIS BE 78 ARG LEU 82 HIS ASN 76 HIS BE 78 ARG LEU 82 TYR ASN 76 H1S SER 78 ASP LEU 82 PHE ASN 76 HIS BE 78 ASP LEU 82 H? S ASN 76 HIS BE 78 ASP LEU 82 T? R ASN 76 HIS SER 78 GLN LEU 82 PHE ASN 76 HIS SER 78 GLN LEU 82 H? S ASN 76 HIS BE 78 GLN LEU 82 TYR ASN 76 HIS BE 78 HIS LEU 82 PHE ASN 76 HIS BE 78 HIS LEU 82 HIS ASN 76 HIS BE 78 H? S LEU 82 TYR ASN 76 HIS BE 78 LYS LEU 82 PHE ASN 76 HIS BE 78 LYS LEU 82 HIS ASN 76 HIS BE 78 LYS LEU 82 TYR ASN 76 HIS BE 78 TYR LEU 82 PHE ASN 76 HSS BE 78 TYR LEU 82 HIS ASN 76 HIS BE 78 TYR LEU 82 TYR ASN 76 HIS BE 78 ASN VAL 81 THR ASN 76 H? S BE 78 THR VAL 81 THR ASN 76 HIS BE 78 ARG VAL 81 THR ASN 76 HIS BE 78 ASP VAL 81 THR ASN 76 HIS BE 78 GLN VAL 81 THR ASN 76 HIS BE 78 HIS VAL 81 THR ASN 76 HIS BE 78 LYS VAL 81 THR ASN 76 H? S BE 78 TYR VAL 81 THR ASN 76 HiS SER 78 ASN LE 79 LEU ASN 76 HI S SER 78 ASN ILE? MET ASN 76 HIS BE 78 ASN LE 79 THR
ASN 76 HIS BE 78 ASN ILE 79 VAL ASN 76 HIS BE 78 THR ÍLE 79 LEU ASN 76 H? S BE 78 THR ILE 79 MET ASN 7 HIS BE 78 THR ILE 79 THR ASN 76 HIS BE 78 THR ILE 79 VAL ASN 76 HIS BE 78 ARG ILE 79 LEU ASN 76 HIS BE 78 ARG ILE 79 MET ASN 76 HIS BE 78 ARG LE 79 THR ASN 76 HIS BE 78 ARG ILE 79 VAL ASN 76 HIS BE 78 ASP ILE 79 LEU ASN 76 HIS BE 78 ASP LE 79 MET ASN 76 HIS BE 78 ASP ILE 79 THR
ASN 76 HIS BE 78 ASP HE 79 VAL ASN 76 HIS BE 78 GLN ÍLE 79 LEU ASN 76 HIS BE 78 GLN ILE 79 MET ASN 76 HIS BE 78 GLN ILE 79 THR ASN 76 HIS BE 78 GLN? LE 79 VAL 1 ASN 76 HIS BE 78 HIS ILE 79 LEU ASN 76 HIS BE 78 HIS ILE 79 MET ASN 76 HIS BE 78 HIS LE 79 THR ASN 76 H? S BE 78 HIS? LE 79 VAL ASN 76 HIS BE 78 LYS ILE 79 LEU ASN 76 HIS BE 78 LYS ILE 79 MET ASN 76 HIS BE 78 LYS LE 79 THR ASN 76 HIS BE 78 LYS ELE 79 VAL
ASN 76 HIS BE 78 TYR ILE 79 LEU ASN 76 HIS BE 78 T? R ILE 79 MET ASN 76 HIS BE 78 TYR ILE 79 THR ASN 76 HIS BE 78 TYR ILE 79 VAL LEU 75 ILE VAL 81 THR LEU 82 PHE LEU 75 ILE VAL 81 THR LEU 82 HIS LEU 75 LE VAL 81 THR LEU 82 T? R LEU 75 MET VAL 81 THR LEU 82 PHE LEU 75 MET VAL 81 THR LEU 82 HIS LEU 75 MET VAL 81 THR LEU 82 TYR LEU 75 VAL VAL 81 THR LEU 82 PHE LEU 75 VAL VAL 81 THR LEU 82 HIS LEU 75 VAL VAL 81 THR LEU 82 TYR LEU 75 LE ILE 79 LEU LEU 82 PHE LEU 75 ILE ILE 79 LEU LEU 82 H1S LEU 75 ILE ILE 79 LEU LEU 82 TYR LEU 75 ILE ILE 79 MET LEU 82 PHE LEU 75 ILE ILE 79 MET LEU 82 H1S LEU 75 ILE ILE 79 MET LEU 82 TYR LEU 75 ILE? LE 7 TH LEU 82 PHE LEU 75 ILE? LE 79 THR LEU 82 HIS LEU 75 1LEILE 79 THR LEU 82 TYR LEU 75 ILE? LE 79 VAL LEU 82 PHE LEU 75 ILE ILE 79 VAL LEU 82 HIS LEU 75 ILE ILE 79 VAL LEU 82 TYR LEU 75 MET ILE 79 LEU LEU 82 PHE LEU 75 MET ILE 79 LEU LEU 82 HIS LEU 75 MET LE 79 LEU LEU 82 TYR LEU 75 METELE 79 MET LEU 82 PHE LEU 75 MET LE 79 MET LEU 82 H? S
LEU 75 MET LE 79 MET LEU 82 TYR LEU 75 ET 1LE 79 THR LEU 82 PHE LEU 75 MET LE 79 THR LEU 82 HIS LEU 75 MET LE 79 THR LEU 82 TYR LEU 75 MET LE 79 VAL LEU 82 PHE LEU 75 MET ILE 79 VAL LEU 82 HIS LEU 75 MET 1LE 79 VAL LEU 82 TYR LEU 75 VAL ILE 79 LEU LEU 82 PHE LEU 75 VAL LE 79 LEU LEU 82 HIS LEU 75 VAL LE 79 LEU LEU 82 TYR LEU 75 VAL LE 79 MET LEU 82 PHE LEU 75 VAL ILE 79 MET LEU 82 H? S LEU 75 VAL ILE 79 MET LEU 82 TYR
LEU 75 VAL LE 79 TH LEU 82 LE LE 75 75 LE LE 75 LE LE 75 75 LE LE 75 LE LE 75 75 LE LE 75 LE LE 75 75 LE LE 75 LE LE 75 LE LE 75 75 VAL LE LE 75 LEU 75 VAL HE 79 VAL LEU 82 TYR LEU 75 LE LE 79 LEU VAL 81 THR LEU 75 ILE LE 79 MET VAL 81 THR LEU 75 LE LE 79 THR VAL 81 THR LEU 75 ILE ELE 79 VAL VAL 81 THR LEU 75 MET LE 79 LEU VAL 81 THR LEU 75 MET LE 79 MET VAL 81 THR
LEU 75 MET LE 79 THR VAL 81 THR LEU 75 MET? LE 79 VAL VAL 8¡ THR LEU 75 VALILE 79 LEU VAL 1 THR LEU 75 VAL ILE 79 MET VAL 81 THR LEU 75 VALILE 79 THRVAL 81 THR LEU 75 VAL ILE 79 VAL VAL 81 THR LEU 75? LE SER 78 ASN LEU 82 PHE LEU 75 ILE SER 78 ASN LEU 82 HIS LEU 75 ILE SER 78 ASN LEU 82 TYR LEU 75 ILE SER 78 THR LEU 82 PHE LEU 75 LE BE 78 THR LEU 82 H1S LEU 75 WILL BE 78 THR LEU 82 T? R LEU 75 ILE BE 78 ARG LEU 82 PHE LEU 75 1LE BE 78 ARG LEU 82 HIS LEU 75 ILE BE 78 ARG LEU 82 TYR LEU 75 ILE BE 78 ASP LEU 82 PHE LEU 75 ¡LE BE 78 ASP LEU 82 HJS LEU 75 ILE BE 78 ASP LEU 82 TYR LEU 75 ILE SER 78 GLN LEU 82 PHE LEU 75? LE SER 78 GLN LEU 82 HIS LEU 75 ¡LE SER 78 GLN LEU 82 TYR LEU 75 ILE BE 78 HIS LEU 82 PHE LEU 75 I WILL BE 78 HiS LEU 82 HIS LEU 75 I WILL BE 78 HIS LEU 82 TYR LEU 75 ILE BE 78 LYS LEU 82 PHE LEU 75 ILE BE 78 LYS LEU 82 HIS LEU 75 ILE BE 78 LYS LEU 82 T? R LEU 75 WILL BE 78 TYR LEU 82 PHE LEU 75 WILL BE 78 TYR LEU 82 HIS L EU 75 ILE BE 78 T? R LEU 82 TYR LEU 75 MET BE 78 ASN LEU 82 PHE LEU 75 MET BE 78 ASN LEU 82 HIS
LEU 75 MET BE 78 ASN LEU 82 TYR LEU 75 MET BE 78 THR LEU 82 PHE LEU 75 MET BE 78 THR LEU 82 HiS LEU 75 MET BE 78 THR LEU 82 TYR LEU 75 MET BE 78 ARG LEU 82 PHE LEU 75 MET SER 78 ARG LEU 82 HIS LEU 75 MET BE 78 ARG LEU 82 TYR LEU 75 MET BE 78 ASP LEU 82 PHE LEU 75 MET BE 78 ASP LEU 82 HIS LEU 75 MET BE 78 ASP LEU 82 TYR LEU 75 MET SER 78 GLN LEU 82 PHE LEU 75 MET SER 78 GLN LEU 82 HIS
LEU 75 MET BE 78 GLN LEU 82 T? R LEU 75 MET BE 78 HIS LEU 82 PHE LEU 75 MET BE 78 H1S LEU 82 HIS LEU 75 MET BE 78 HJS LEU 82 TYR LEU 75 MET BE 78 LYS LEU 82 PHE LEU 75 MET BE 78 LYS LEU 82 HIS LEU 75 MET BE 78 LYS LEU 82 TYR LEU 75 MET BE 78 T? R LEU 82 PHE LEU 75 MET BE 78 TYR LEU 82 HIS LEU 75 MET BE 78 TYR LEU 82 TYR LEU 75 VAL SER 78 ASN LEU 82 PHE LEU 75 VAL SER 78 ASN LEU 82 HIS LEU 75 VAL SER 78 ASN LEU 82 TYR
LEU 75 VAL SER 78 THR LEU 82 PHE LEU 75 VAL SER 78 THR LEU 82 HIS LEU 75 VAL SER 78 THR LEU 82 TYR LEU 75 VAL SER 78 ARG LEU 82 PHE LEU 75 VAL SER 78 ARG LEU 82 HIS LEU 75 VAL SER 78 ARG LEU 82 TYR LEU 75 VAL SER 78 ASP LEU 82 PHE LEU 75 VAL SER 78 ASP LEU 82 HIS LEU 75 VAL SER 78 ASP LEU 82 TYR LEU 75 VAL SER "8 GLN LEU 82 PHE LEU 75 VAL SER 78 GLN LEU 82 HIS LEU 75 VAL SER 78 GLN LEU 82 TYR LEU 75 VAL SER 78 HIS LEU 82 PHE LEU 75 VAL SER 78 HIS LEU 82 H1S LEU 75 VAL SER 78 HIS LEU 82 TYR LEU 75 VAL SER 78 LYS LEU 82 PHE LEU 75 VAL SER 78 LYS LEU 82 H1S LEU 75 VAL SER 78 LYS LEU 82 TYR LEU 75 VAL SER 78 TYR LEU 82 PHE LEU 75 VAL SER 78 TYR LEU 82 HJS LEU 75 VAL SER 78 TYR LEU 82 TYR LEU 75 LE SER 78 ASN VAL 81 THR 75 IT WILL BE 78 THR VAL 81 THR LEU 75 ILE BE 78 ARG VAL 81 THR LEU 75 ILE BE 78 ASP VAL 81 THR LEU 75 ILE BE 78 GLN VAL SI THR LEU 75 1LE SER 78 HIS VAL 81 THR LEU 75? LE SER 78 LYS VAL 81 THR LEU 75 ILE SER 78 TYR VAL 1 THR LEU 75 MET SER 78 ASN VAL 81 THR
LEU 75 MET SER 78 TOR VAL 81 THR LEU 75 MET SER 78 ARG VAL 81 THR LEU 75 MET SER 78 ASP VAL 81 THR LEU 75 MET SER 78 GLN VAL 1 THR LEU 75 MET SER 78 HIS VAL ti THR LEU 75 MET SER 78 LYS VAL 1 THR LEU 75 MET SER 78 TYR VAL 81 THR LEU 75 VAL SER 78 ASN VAL 81 THR LEU 75 VAL SER 78 THR VAL 81 THR LEU 75 VAL SER 78 ARG VAL 81 THR LEU 75 VAL SER 78 ASP VAL 81 THR LEU 75 VAL SER 78 GLN VAL 81 THR LEU 75 VAL SER 78 HIS VAL 81 THR
LEU 75 VAL SER 78 LYS VAL 81 THR LEU 75 VAL SER 78 TYR VAL SI THR LEU 75 ILE SER 78 ASN LE 79 LEU LEU 75 1LE SER 78 ASN? LE 79 MET LEU 75 ILE SER 78 ASN ÍLE 79 THR LEU 75 ÍLE SER 78 ASN ILE 79 VAL LEU 75 ILE BE 78 THR ILE 79 LEU LEU 75 ILE BE 78 THR? LE 79 MET LEU 75 DLE SER 78 THR ILE 79 THR LEU 75 ILE SER 78 THR? LE 79 VAL LEU 75 ILE SER 78 ARG LE 79 LEU LEU 75 ILE BE 78 ARG ILE 79 MET LEU 75 ÍLE SER 78 ARG ÍLE 79 THR
LEU 75 WILL BE 7g ARG 1LE 79 VAL LEU 75 1LE BE 78 ASP ILE 79 LEU LEU 75 ILE BE 78 ASP ILE 79 MET LEU 75 ILE BE 78 ASP LE 79 THR LEU 75 ILE BE 78 ASP ILE 79 VAL LEU 75 ILE BE 78 GLN LE 79 LEU LEU 75 I WILL BE 78 GLN ILE 79 MET LEU 75 ILE BE 78 GLN LE 79 THR LEU 75 I WILL BE 78 GLN LE 79 VAL LEU 75 I WILL BE? HiS? L £ '9 LEU LEU 75 ILE SER ~ S HiS? LE 79 MET LEU 75 I WILL BE 78 HIS LE 79 THR LEU 75 I WILL BE 78 HIS ILE 79 VAL LEU 75 ILE BE 78 LYS LE 79 LEU LE 75 HE BE 78 LYS HE 79 ÍMET LEU 7J ELI SER 78 LYS HE 79? HR LEU 75 ÍLE SER 7S LYS ILE 7 VAL LEU 75 ILE SER 78 TYR HE 79 LEU LEU 75 ILE SER 78 TYR HE 79 MET LEU 75 HE BE 78 TYR HE 79 THR LEU 75 HE BE 78 TYR HE 79 VAL LEU 75 MET BE 78 ASN HE 79 LEU LE 75 MET BE 78 ASN HE 7 »MET LEU 75 MET BE 78 ASN HE" TUR LEU 75 MET SER 7g ASN HE '9 VAL LEU 75 MET BE 78 THR ÍLM 79 LEU LEU 75 MET BE 78 THR HE 7 MET LEU 75 MET BE 78 T? HE 7 T? R LEU 75 MET BE 78 THR HE 79 VAL LEU MET SER 78 ARG HE 79 LEU
LEU 75 MET BE 78 ARG ÍLE 79 MET LEU 75 MET BE 78 ARG HE 79 THR LEU 75 MET BE 78 ARG ÍLE 79 VAL LEU 75 MET BE 78 ASP HE 79 LEU LEU 75 MET BE 78 ASP HE? 9.MET LEU 75 MET BE 78 ASP HE 79 THR LEU 75 MET BE 78 ASP LEE 79 VAL LEU 75 MET BE 78 GLN ILE 79 LEU 75 MET BE 78 GLN HE? 9 MET LEU 75 MET SER 78 GLN HE HR LEU 75 MET SER 78 GLN HJS 79 VAL LEU 75 MET BE 7S HIS HE? 9 LEU LEU 75 MET BE 78 H? S HE 79 MET
LEU 75 MET BE 7S HS HE 7 THR LEU 75 MET BE 78 HIS HE 79 VAL LEU 75 MET BE 78 LYS ILE 79 LEU LEU 75 MET BE 78 LYS HE 79 MET LINE 75 MET BE 78 LYS HE * 9 THR LSJ 75 MET BE 78 LYS? LE 79 VAL LEU 75 MET BE 78 TYR HE 79 LEU LEU 75 MET BE 78 TYR HE 79 MET LEU 75 MET BE 78 TYR HE 79 THR LEU 75 MET BE 78 T? R JLE 79 VAL LEU 75 VAL SER 78 ASN HE 79 LEU LEU 75 VAL SER 78 ASN HE 79 MET LEU 75 VAL SER? S ASN HE 79 THR
LEU 75 VAL SER 78 ASN HE 79 VAL LEU 75 VAL SER 78 THR HE 79 LEU LEU 75 VAL SER 78 THR LE 79 MET LEU 75 VAL SER 78 THR LE 79 THR LEU 75 VAL SER 78 THR HE 9 VAL LEU 75 VAL SER 78 ARG LE 79 LEU 75 VAL SER 7S? RÚ ILE '9 MET LEU 5 VAL SER 78 ARG LE 79 TOR LEU 75 VAL SER 7S ARG ÍLE 79 VAL LEU 75 VAL SER 78 ASP LE 79 LEU LEU 75 VAL SER 78 ASP HE 79 MET LEU 75 VAL SER 78 ASP LE 79 THR LEU 75 VAL SER 78 ASP LE 79 VAL LEU 75 VAL SER 78 GLN? LE 79 LEU LEU 75 VAL SER 78 GLN ILE 79 MET LEU 75 VAL SER 78 GLN ÍLE 79 THR LEU 75 VAL SER 78 GLN? LE 79 VAL LEU 75 VAL SER 78 HIS HE 79 LEU LEU 75 VAL SER 78 HIS LE 79 MET LEU 75 VAL SER 78 HIS HE 79 TOR LEU 75 VAL SER 78 HIS HE 79 VAL LEU 75 VAL SER 78 LYS ÍLE 79 LEU LEU 75 VAL SER 78 LYS ILE 79 MET LEU 75 VAL SER 78 LYS HE 79 THR LEU 75 VAL SER 78 LYS LE 79 VAL LEU 75 VAL SER 78 TYR ÍLE 79 LEU LEU 75 VAL SER 78 T? R LE 79 MET LEU 75 VAL SER 78 TYR HE 79 TOR LEU 75 VAL SER 78 TYR HE 79 VAL LEU 75 HE ASN 76 H1S LEU 82 PHE LEU 75 HE ASN 76 HIS LEU 82 HIS
LEU 75 ILE ASN 76 HIS LEU 82 TYR LEU 75 MET ASN 76 HIS LEU 82 PHE LEU 75 MET ASN 76 H? S LEU 82 H1S LEU 75 METASN 76 HIS LEU 82 TYR LEU 75 VAL ASN 76 HIS LEU 82 PHE LEU 75 VAL ASN 76 HIS LEU 82 HIS LEU 75 VAL ASN 76 HIS LEU 82 TYR LEU 75 HE ASN 76 HIS VAL 8! THR LEU 75 MET ASN 76 HIS VAL 81 TOR LEU 75 VAL ASN 76 HIS VAL 81 TOR LEU 75 HE ASN 76 HIS? LE 79 LEU LEU 75 ÍLE ASN 76 HIS? LE 79 MET LEU 75 HE ASN 76 H? S HE 79 THR
LEU 75 ILE ASN 76 HIS ILE 79 VAL LEU 75 MET ASN 76 HIS HE 7 LEU LEU 75 MET ASN 76 HIS ILE 79 MET LEU 75 MET ASN 76 HIS HE 79 TOR LEU 75 MET ASN 76 HIS? LE 79 VAL LEU 75 VAL ASN 76 HISELE 79 LEU LEU 75 VAL ASN 76 H? S HE 79 MET LEU 75 VAL ASN 76 H? S HE 79 THR LEU 75 VAL ASN 76 HIS? LE 79 VAL LEU 75 HE ASN 76 HIS BE 78 ASN LEU 75 HE ASN 76 HIS BE 78 THR LEU 75 HE ASN 76 HIS BE 78 ARG
LEU 75 LE ASN 76 HIS BE 78 ASP LEU 75 ILE ASN 76 H? S BE 78 GLN LEU 75 ILE ASN 76 HIS BE 78 HIS LEU 75 ILE ASN 76 HIS BE 78 LYS LEU 75 ILE ASN 76 HIS BE 78 TYR LEU 75 MET ASN 76 HIS BE 78 ASN LEU 75 MET ASN 76 HIS BE 78 TOR LEU 75 MET ASN 76 HIS BE 78 ARG LEU 75 MET ASN 76 HIS BE 78 ASP LEU- 75 MET ASN 76 HIS BE 7S GLN LEU 75 MET ASN 76 HIS BE 78 HiS LEU 75 MET ASN 76 H¡S SER '8 LYS LEU 75 MET ASN 76 HiS SER 78 TYR LEU 75 VAL ASN 76 HiS SER 78 ASN LEU 75 VAL ASN 76 HIS SERIOUS LEU 75 VAL ASN 76 HiS SER 78 ARG LEU 75 VAL ASN 76 H? S SER 78 ASP LEU 75 VAL ASN 76 HJS SER 78 GLN LEU 75 VAL ASN 76 H1S SER 78 H? S LEU 75 VAL ASN 76 HIS SER 78 LYS LEU 75 VAL ASN 76 H1S SER / * TYR TABLE 5 Replacement variants quadruple SER 78 ASN ILE 79 LEU VAL 81 THRLEU 82 PHE SER 78 ASN ILE 79 LEU VAL 8 i THR EU 82 HIS BE 78 ASN HE 79 LEU VAL 81 THR EU 82 TYR BE 78 SNILE 79 MET VAL 8? THRLEU 82 PHE SER 78 ASN BLE 79 MET VAL 81 THRLEU 82 HiS
SER 78 ASN ELE 79 MET VAL Yes THR LEU 82TYR BE 78 ASN? LE 79 THR VAL 81 THR LEU 82 PHE SER 71 ASN? LE 79 THR VAL 81THRLEU 82HIS SER 78 ASN ILE 79 THR VAL 8! THR LEU 82 TYR SER 78ASN1LE 79 VAL VAL 81 THRLEU 82 PHE SER 78 ASN? LE 79 VAL VAL 81 THRLEU 82HIS SER 78 ASN HE 79 VAL VAL 81 THRLEU 82 TYR SER 78 THR ILE 79 LEU VAL 81 THRLEU 82 PHE SER 78THRILE 79 LEU VAL 81 THRLEU 82HIS BE 78 THR ÍLE 79 LEU VAL SI THR LEU 82TYR BE 78 THR ILE 79 MET VAL TH LEU 82 PHE SER 71 THR ILE 79 MET VAL 81 THRLEU 82HIS
SER 7S THR ÍLE 79 MET VAL The THR LEU 82 TYR BE 78 TUR HE 79 THR VAL 8! THRLEU 82 PHE SER 7? THR E.E 79 THR VAL t! TH LEU 82 H? S BE 7S THR ILE 79 THR VAL 81 TH LEU 82 TYR SER 7TTHRILE 79 VAL VAL S? TH LEU 82 PHE SER 71 THR ÍLE 79 VAL VAL 8? TH LEU 8 HIS SER 78 THR HE 79 VAL VAL 81 THRLEU 82TYR BE 78 ARG HE 79 LEU VAL 81 THRLEU S2 PHI? SER? S ARGILE 79 LEU VAL 81 THRLEU 82HIS BE IT A GILE 79 LEU VAL 81 TH LEU 82 TYR SER 78 ARG ÍLE 79 MET VAL 81 THRLEU 82 PHE SER 71 ARG ILE 79 MET VAL 81 THR LEU 82HIS
SER 78 ARG ILE 79 MET VAL 8t THRLEU 82 TYR SER 78 ARG iLE 79TH VAL 81 THR LEU S2 P.HLE SER 78 ARG HE 79 THR VAL 81 THRLEU 82 MS SER 78 ARG ILE 79 THR VAL 81 THR LEU 82 TYR SER 78 ARG ILE 79 VAL VAL 81 THRLEU 82 PHE SER 78 ARG ILE 79 VAL VAL 81 THR LEU 82HIS SER 78 ARG? LE 79 VAL VAL 81 THR LEU 82 TYR SER 8 ASP ÍLE 79 LEU VAL 8! THRLEU 82 PHE SER? S ASP? LE 79 LEU VAL 81 THR LEU 82 HERE TO BE 78 ASPÃLE 79 LEU VAL 8? THRLEU 82 TYR BE 78 ASP HE 70 MET VAL 81 THRLEU 82 PHE SER 78 ASP LE 79 MET VAL 81 THR LEU 82 HIS BE 78 ASP JLE 79 MET VAL 81 THR LEU 82 TYR BE 78 ASP HE 79 TOR VAL 81 THRLEU 82 PHE BE 78 ASP HE 79 TOR VAL 81 THRLEU 8 HIS BE 78 ASP HE 79 TOR VAL 81 THRLEU 82TYR BE 78 ASP HE 79 VAL VAL Yes THRLEU 82 PHE SER 78 ASP ILE 79 VAL VAL 81 THR LEU 82H? S BE 78 ASP? LE 79 VAL VAL 81 THR LEU 82TYR SER 78 GLN HE 79 LEU VAL 81 THR LEU 82 PHE SER 78 GLN ILE 79 LEU VAL 81 THR LEU 82 HIS SER 78 GLN ILE 79 LEU VAL 81 THR LEU 82 T? R SER 78 GLN ÍLE 79 MET VAL 81 THR LEU 82 PHE SER 78 GLN HE 79 MET VAL 81 THRLEU 82 HIS SER 78 GLN LE MET VAL 81 THR LEU 82 T? R SER 78 GLN INE 79 TOR VAL 81 THR LEU 82 PHE SER 78 GLN HE 7 THRVAL 8ÍTHRLEU 82 H1S SER 78 GLN HE 79 THR VAL 81 THR LEU 82 TYR SER 78 GLN ILE 79 VAL VAL 81 THR LEU 82 PHE SER 78 GLN ILE 79 VAL VAL 81 THR LEU 82 H? S SER 78 GLN HE 79 VAL VAL 81 THR EU 82 TYR BE 78 HIS HE 79 LEU VAL 81 THRLEU 82 PHE SER 78 H1S? LE 79 L EU VAL 81 THR LEU 82 HIS
SER 78 H? S HE 79 LEU VAL 81 THR LEU 82 TYR SER 78 HIS HE 79 MET VAL 81 THR LEU 82 PHE SER 78 HiS HE 79 MET VAL 81 THR LEU 82 HIS SER 78 HIS HE 79 MET VAL 81 THR LEU 82 T? R SER 78 H1S ILE 79 TOR VAL 81 THR LEU 82 PHE SER 78HISHE 79 TOR VAL 81 TH LEU 82 HIS SER 78HISHE 79 TOR VAL 81 TH LEU 82 TYR SER 78 HIS HE 79 VAL VAL 81 THR LEU 82 PHE SER 78 H ? S HE 79 VAL VAL 81 THRLEU 82 HIS BE 78 H? S HE 79 VAL VAL 81 THR LEU 82 T? R SER 78 LYS HE 79 LEU VAL 81 THR LEU 82 PHE SER 78 LYS HE 79 LEU VAL 81 THRLEU 82 HIS
SER 78 LYS HE 79 LEU VAL 81 THR LEU 82 TYR SER 78 LYS? LE 79 MET VAL 81 THR LEU 82 PHE SER 78 LYS HE 79 MET VAL 81 THR LEU 82 HIS SER 78 LYS ÍLE 79 MET VAL 81 THRLEU 82 TYR SER 78 LYS? LE 79 THR VAL 81 THR LEU 82 PHE SER 78 LYS HE 79 THR VAL 81 THRLEU 82H1S SER 78 LYS ILE 79 TOR VAL 81 THR LEU 82 TYR SER 78 LYS HE 79 VAL VAL 81 THRLEU 82 PHE 'SER 78 LYS ILE 79 VAL VAL 81 THRLEU 82HIS SER 78 LYS ILE 79 VAL VAL 81 HRLEU 82 TYR SER 78 TYR ÍLE 79 LEU VAL 81 THRLEU 82 PHE SER 78 TYR HE 79 LEU VAL 81 THRLEU 82HIS SER 78 TYR HE 79 LEU VAL 81 THR LEU 82 YR
SER 78 TYR ILE 79 MET VAL 81 THR LEU 82 PHE SER 78 TYR HE 79 MET VAL 81 THR EU 82HIS BE 78 TYR HE 79 MET VAL 81 THR LEU 82 TYR BE 78 TYR HE 79 TOR VAL 81 TH LEU 82 PHE SER 78 TYR LE 79 THR VAL 81 THR LEU 82 HH S SER 78TYRILE 79 TOR VAL 81 THRLEU 82 TYR BE 78 TYR HE 79 VAL VAL S 1 TOR LEU 82 PHE SER 7 TYRILE 79 VAL VAL 81 TH LEU 82H1S SER 78 TYR ILE 79 VAL VAL 81 TOR LEU 82TYR ASN 76 HISELE 79 LEU VAL 8,1 THR LEU 82 PHE ASN 76 HiS LE 79 LEU VAL 8! TH LEU 82HIS ASN 76 HIS HE 79 LEU VAL 81 TH LEU 82TYR ASN 76 H? S LE 79 MET VAL 81 THRLEU 82 PHE ASN 76 HIS LE 79 MET VAL 81 TOR LEU S2HIS ASN 76 HIS LE 79 MET VAL 81 THRLEU 82TYR ASN 76 HIS LE 79 TOR VAL 81 TOR LEU 82 PHE ASN 76 HIS HE 79 THR VAL 8 THR LEU 82H1S ASN 76 HISELE 79 THR VAL 81 THR LEU 82 TYR ASN 76 HISELE 79 VAL VAL 81 THRLEU * > 2 P ic ASN 76 HIS ILE 79 VAL VAL 81 TOR LEU 82HIS ASN 76H1SILE 79 VAL VAL 81TH LEU 82TYR ASN 76 HiS SER 78 ASN VAL 81 THR LEU 82 PHE ASN 76 H? S SER 78 ASN VAL 81 TOR LEU 82HIS ASN 76 HIS SER 78 ASN VAL 81 THRLEU 82 TYR ASN 76 HIS SER 78 THR VAL 81 TOR LEU 82 PHE ASN 76 HIS SER 78 TOR VAL 81 TH LEU ASN 76 HERE BE 78 THR VAL 81 TOR LEU 82 »TYR ASN 76 H1S SER 78 ARG VAL 81 TOR LEU 82 PHE
ASN 76 HIS BE 78 ARG VAL 81 TOR LEU 82HIS ASN 76 H1S BE 78 ARG VAL 8! TOR LEU 82TYR ASN 7 HISSER 78 ASP VAL 81 TOR LEU 82 PHE ASN 76 HIS SER 8 ASP VAL 81 THR LEU 82HIS ASN 76 H? S SER 78 ASP VAL 81 THRLEU 82TYR ASN 76 HIS SER 78 GLN VAL 81 THRLEU 82 PHE ASN 76 H1S SER 78 GLN VAL 81 TOR LEU 82HIS ASN 76 HIS SER 78 GLN VAL 81 THRLEU 82 TYR ASN 76 H? S SER 78 HIS VAL 81 TOR LEU 82 PHE ASN 76 HIS BE 78 H? S VAL 81 THRLEU 82HIS ASN 76 H1S SER 78 HIS VAL If TOR LEU 82 TYR ASN 76 HIS BE 78 LYS VAL 81 TOR LEU 82 PHE ASN 76 HiS SER 78 LYS VAL 81 TH LEU 82H1S
ASN 76 HIS BE 78 LYS VAL 81 TOR LEU 82 TYR ASN 76 HIS SER 78 TYR VAL 81 TOR LEU 82 PHE ASN 76 H1S SER 78 TYR VAL 81 THRLEU 82HIS ASN 76 H1S SER 78 TYR VAL 81 TOR LEU 82 YR ASN 76 HIS BE 78 ASN HE 79 LEU LEE 82 PHE ASN 76 HIS BE 78 ASN HE 79 LEU LEU 82HIS ASN 76 HIS BE 78 ASN HE 79 LEU LEU 82TYR ASN 76 HIS BE 78 ASN HE 79 MET LEU 82 PHE ASN 76 HIS BE 78 ASN HE 79 MET LEU 82HIS ASN 76 HIS BE 78 ASN HE 79 MET LEU 82 TYR ASN 76 H? S BE 78 ASN? LE 79 THR LEU 82 PHE ASN 76 H? S BE 78 ASN HE 79 TOR LEU 82HIS ASN 76 HIS BE 78 ASN HE 79 TOR LEU 82 TYR
ASN 76HISSER 78 ASN HE 79 VAL LEU 82 PHE ASN 76 H1S SER 78 ASN ILE 79 VAL LEU 82HIS ASN 76 HIS SER 78 ASN HE 79 VAL LEU 82 TYR ASN 76 H? S SER 78 TOR HE 79 LEU LEU 82 PHE ASN 76HISSER 78 TOR HE 79 LEU LEU 82 HiS ASN 76 H? S BE 78 THR HE 79 LEU LEU 82 TYR ASN 76 H? S BE 78 THR? 79 MET LEU 82 PHE ASN 76 HiS SER 78 THR HE 79 MET LEU 82HIS ASN 76 HIS BE 78 THR LE 79 MET LEU 82 TYR ASN 76 H? S BE 78 THR LE 79 THR LEU 82 PHE ASN 7 HERE BE 78 THR HE ~ 9 THR LEU 82 H1S ASN 76 H? S BE 78 THR HE 79 THR LEU 82 TYR ASN 76 HIS BE 78 THR LE 79 VAL LEU 82 PHE ASN 76 H? S BE 78 THR LE 79 VAL LEU 82 H1S ASN 76 HERE BE 78 THR HE 79 VAL LEU 82 TYR ASN 76 HiS SER 8 ARG HE 79 LEU LEU 82 PHE ASN 76 HIS BE 78 ARG HE 79 LEU LEU 82 HIS ASN 76 H? S BE 78 ARG HE 79 LEU LEU 82 TYR ASN 76 HIS BE 7 $ ARG? LE 79 MET LEU 82 PHE ASN 76 HIS BE 78 ARG ILE 79 MET LEU 82 HIS ASM 76 H? S BE 78 ARG HE 79 MET LEU 82 T? R ASN 76 HIS BE 78 ARG? LE 79 THR LEU 82 PHE ASN 76 HIS BE 78 AR G HE 79 THR LEU 82 HIS ASN 76 HIS BE 78 ARG LE 79 TOR LEU 82 TYR ASN 76 HIS BE 78 ARG HE 79 VAL LEU 82 PHE ASN 7 HS BE 78 ARG HE 79 VAL LEU 82 H1S ASN 76 HIS BE 78 ARG HE 79 VAL LEU 82 TYR ASN 76 HIS BE 78 ASP? LE 79 LEU LEU 82 PHE ASN 76 HIS BE 78 ASP HE 79 LEU LEU 82 H? S ASN 76 HiS SER 78 ASP HE 79 LEU LEU 82 TYR ASN 76 HiS SER 78 ASP 1LE 79 MET LEU 82 PHE
ASN 76 HIS BE 78 ASP ILE 79 MET LEU 82 H1S ASN 76 HIS BE 78 ASP LE 79 MET LEU 82 TYR ASN 7 HIS BE 78 ASP HE 79 THR LEU 82 PHE ASN 76 H? S BE 78 ASP 1LE 79 TOR LEU 82 HIS ASN 7 HTS BE 78 ASP HE 79 TOR LEU 82 TYR ASN 76 HIS BE 78 ASP LE 79 VAL LEU 82 PHE ASN 76 H1S SER 78 ASP HE 79 VAL LEU 82 HIS ASN 76 HIS BE 78 ASP HE 79 VAL LEU 82 TYR ASN 76 HIS SER 78 GLN? LE 79 LEU LEU 82 PHE ASN 76 HIS SER 78 GLN HE 79 LEU LEU 82 H1S ASN 76 HIS SER 78 GLN HE 79 LEU LEU 82 TYR ASN 76 HIS SER 78 GLN ILE 79 MET LEU 82 PHE
ASN 76 H? S BE 78 GLN HE 79 MET LEU 82 HIS ASN 76 H? S BE 78 GLN ILE 79 MET LEU 82 TYR ASN 76 H1S SER 78 GLN HE 79 TOR LEU 82 PHE ASN 76 HIS SER 78 GLN LE 79 THR LEU 82 H1S ASN 76 HIS SER 78 GLN HE 79 THR LEU 82 TYR ASN 76 HIS SER 78 GLN ILE 79 VAL LEU 82 PHE ASN 76 HIS SER 78 GLN HE 79 VAL LEU 82 HIS ASN 76 HIS SER 78 GLN HE 79 VAL LEU 82 TYR ASN 76 H? S BE 78 HIS ILE 79 LEU LEU 82 PHE ASN 76 HIS BE 78 H? S ILE 79 LEU LEU 82 HIS ASN 76 HIS BE 78 HIS HE 79 LEU LEU 82 TYR ASN 76 HIS BE 78 HIS HE 79 MET LEU 82 PHE ASN 76 HIS BE 78 HIS HE 79 MET LEU 82 HIS
ASN 76 H1S BE 78 HIS HE 79 MET LEU 82 TYR ASN 76 HIS BE 78 HIS HE 79 THR LEU 82 PHE ASN 76 HIS BE 78 H? S ILE 79 THR LEU 82 HIS ASN 76 HIS BE 78 H1S HE 79 THR LEU 82 TYR ASN 76 HIS BE 78 HIS 1LE 79 VAL LEU 82 PHE ASN 76 H1S SER 78 H1S ÍLE 79 VAL LEU 82 HIS ASN 76 H1S SER 78 H1S? LE 79 VAL LEU 82 TYR ASN 76 HIS SER 78 LYS HE 79 LEU LEU 82 PHE ASN 76 H? S BE 78 LYS HE 79 LEU LEU 82 HIS ASN 76 HIS BE 78 LYS HE 79 LEU LEU 82 TYR ASN 76 HIS BE 78 LYS ILE 79 MET LEU 82 PHE ASN 76 HIS BE 78 LYS ILE 79 MET LEU 82 H1S ASN 76 H? S BE 78 LYS LE 79 MET LEU 82 TYR ASN 76 HIS BE 78 LYS HE 79 THR LEU 82 PHE ASN 76 HIS BE 78 LYS HE 79 THR LEU 82 HiS ASN 76 HIS BE 78 LYS HE 79 THR LEU 82 TYR ASN 76 HIS BE 78 LYS ILE 79 VAL LEU 82 PHE ASN 76 H1S SER 78 LYS ILE 79 VAL LEU 82 HIS ASN 76 H1S SER 78 LYS? LE 79 VAL LEU 82 TYR ASN 76 HIS SER 78 TYR? LE 79 LEU LEU 82 PHE ASN 76 HIS BE 78 TYR HE 79 LEU LEU 82 HIS ASN 76 H? S BE 78 TYR LE 79 LEU LEU 82 TYR ASN 76 HIS BE 78 TYR ILE 79 MET LEU 82 PHE ASN 76 HIS BE 78 TYR HE 79 MET LEU 82 HIS ASN 76 HIS BE 78 TYR ILE 79 MET LEU 82 TYR ASN 76 H? S BE 78 TYR HE 79 THR LEU 82 PHE ASN 76 HIS BE 78 TYR HE 79 THR LEU 82 HIS ASN 76 HIS BE 78 TYR HE 79 THR LEU 82 TYR ASN 76 HIS BE 78 TYR HE 79 VAL LEU 82 PHE ASN 76 HIS BE 78 TYR HE 79 VAL LEU 82 H¡S
ASN 76 HIS BE 78 TYR ILE 79 VAL LEU 82 TYR ASN 76 H1S BE 78 ASN HE 79 LEU VAL 8! THR ASN 76 HIS SER 78 ASN ILE 79 MET VAL 81 THR ASN 76 HIS SER 78 ASN HE 79 THR VAL 81 THR ASN 76 H? S SER 78 ASN ILE 79 VAL VAL 81 THR ASN 76 HiS SER 78 THR ILE 79 LEU VAL 81 THR ASN 76 HIS BE 78 THR HE 79 MET VAL 81 TOR ASN 76 HIS BE 78 TOR ILE 79 THR VAL 81 THR ASN 76 HIS BE 78 THR HE 79 VAL VAL 81 THR ASN 76 HIS BE 78 ARG HE 79 LEU VAL 81 TOR ASN 76 HIS BE 78 ARG ILE 79 MET VAL 81 THR ASN 76 HIS BE 78 ARG ILE 79 THR VAL 81 TOR ASN 76 HIS SER 78 ARG ILE 79 VAL VAL 81 THR
ASN 76 HIS BE 78 ASP HE 79 LEU VAL 81 THR ASN 76 HIS BE 78 ASP HE 79 MET VAL 81 TOR ASN 76 HIS BE 78 ASP HE 79 THR VAL 81 THR ASN 76 HERE BE 78 ASP HE 79 VAL VAL 81 THR ASN 76 HIS SER 78 GLN HE 79 LEU VAL 81 THR ASN 76 H1S SER 78 GLN? LE 79 MET VAL 81 TOR ASN 76 HIS SER 78 GLN HE 79 THR VAL 81 TOR ASN 76 HIS SER 78 GLN? LE 79 VAL VAL 81 THR ASN 76 HIS BE 78 HIS ILE 79 LEU VAL 81 TOR ASN 76 HiS SER 78 HIS HE 79 MET VAL 81 THR ASN 76 HIS BE 78 HIS ILE 79 THR VAL 81 THR ASN 76 HIS BE 78 HIS HE 79 VAL VAL 81 TOR
ASN 76 HIS BE 78 LYS ILE 79 LEU VAL 81 THR ASN 76 HIS BE 78 LYS HE 79 MET VAL 81 THR ASN 76 HIS BE 78 LYS HE 79 THR VAL 81 THR ASN 76 HIS BE 78 LYS HE 79 VAL VAL 81 THR ASN 76 HIS BE 78 T? R ILE 79 LEU VAL 81 THR ASN 76 HIS BE 78 TYR LE 79 MET VAL 81 THR ASN 76 HERE BE 78 TYR HE 79 THR VAL 81 TOR ASN 76 HIS SER 78 TYR ILE 79 VAL VAL 81 THR LEU 75 HE HE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 HE HE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 HE HE 79 LEU VAL 81 TOR LEU 82 TYR LEU 75 LE LE 79 MET VAL Yes TOR LEU 82 PHE LEU 75 HE HE 79 MET VAL 81 THR LEU S2 H? S LEU 75 1LE? 79 MET VAL 81 TOR LEU 8; TYR LEU 75 ILE ILE 79 THR VAL 81 TOR LEU 82 PHE LEU 75 ILE HE 79 THR VAL 8! THR EU 8 HIS LEU 75 LE LE 79 THR VAL 81 THR EU 82 TYR LEU 75 LE HE 79 VAL VAL 8! TH LEU 82 PHE LEU 75 ILE HE 79 VAL VAL 81 TOR LEU 82 HIS LEU 75 HE HE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 MET HE 79 LEU VAL 81 THR LEU 82 PHE LEU 5 MET? LE 79 LEU VAL 85 TOR LEU 82 HIS LEU 75 MET HE 9 LEU VAL 8 f THR LEU 82 TYR LEU 75 MET LE 79 MET VAL 81 THR LEU 82 PHE LEU 75 METE 79 MET VAL 81 THR LEU 82 HIS LEU 75 MET HE 79 MET VAL 81 TOR LEU 82 TYR LEU 75 MET ILE 79 THR VAL 81 THR LEU 82 PHE LEU 75 MET? LE 79 TOR VAL 81 TOR LEU 82 HIS LEU 75 MET HE 79 TOR VAL 8 i TH LEU 82 TYR LEU 75 MET HE 79 VAL VAL 81 TOR LEU 82 PHE LEU 75 MET HE 79 VAL VAL 81 TOR LEU 82 HIS LEU 75 MET HE 79 VAL VAL 81 THR LEU 82 TYR
LEU 75 VAL ILE 79 LEU VAL 1 THR LEU 82 PHE LEU 75 VAL ILE 79 LEU VAL 81 THR LEU 82 H? S LEU 75 VAL HE 79 LEU VAL 81 TOR LEU 82 T? R LEU 75 VAL HE 79 MET VAL 81 TOR LEU 82 PHE LEU 75 VAL HE 79 MET VAL 81 THR LEU 82 HIS LEU 75 VAL? LE 79 MET VAL 81 THR LEU 82 TYR LEU 75 VAL HE 79 TOR VAL 81 TOR LEU 82 PHE LEU 75 VAL HE 79 THR VAL 81 THR LEU 82 HIS LEU 75 VAL HE 79 THR VAL 81 TOR LEU 82 TYR LEU 75 VAL HE 79 VAL VAL 8 í TOR LEU 82 PHE LEU 75 VAL HE 79 VAL VAL 81 TH LEU S2 HIS LEU 75 VAL HE 79 VAL VAL 8Í THR LEU 82 TYR
LEU 75 HE BE 78 ASN VAL 81 THR LEU 82 PHE LEU 75 HE BE 78 ASN VAL 81 TOR LEU 82 HIS LEU 75 ÍLE SER 78 ASN VAL 81 TOR LEU 82 TYR LEU 75 ILE SER 78 THR VAL 81 TOR LEU 82 PHE LEU 75 ILE BE 78 TOR VAL 81 TH LEU 82 H1S LEU 75 HE BE 78 THR VAL 81 THR LEU S2 TYR LEU 75 HE BE 78 ARG VAL 81 TH LEU 82 PHE LEU 75 1LE SER 78 ARG VAL 81 TOR LEU 82 HiS LEU 75 HE SER 78 ARG VAL 81 THR LEU 82 TYR LEU 75 HE BE 78 ASP VAL 81 TOR LEU 82 PHE LEU 75 HE BE 78 ASP VAL 81 THR LEU 82 HIS LEU 75? LE SER 78 ASP VAL 81 THR LEU 82 TYR LEU 75 HE SER 78 GLN VAL 81 TH LEU 82 PHE
LEU 75 ¡LE SER 78 GLN VAL 81 THR LEU 82 H1S LEU 75 HE BE 78 GLN VAL 81 THR LEU 82 TYR LEU 75 ILE BE 78 HIS VALUE THREE LEU 82 PHE LEU 75 HE BE 78 HIS VAL 8! THR LEU 82 HiS LEU 75 HE BE 78 HIS VAL 81 TOR LEU 82 TYR LEU 75 HE BE 78 LYS VAL 81 TOR LEU 82 PHE LEU 75 HE BE 78 LYS VAL 81 TH LEU 82 HIS LEU 75 LE BE 78 LYS VAL 1 THR LEU 82 TYR LEU 75 HE BE 78 TYR VAL 81 THR LEU 82 PHE LEU 75 HE BE 78 TYR VAL 1 TOR LEU 82 HIS LEU 75 HE BE 78 T? R VAL S! THR LEU 82 T? R LEU 75 MET SER 78 ASN VAL 81 TOR LEU 82 PHE LEU 75 MET SER 78 ASN VAL 81 TOR LEU 82 HIGH LEU 75 MET SER 78 ASN VAL 81 THR LEU 82 TYR LEU 75 MET SER 78 TOR VAL 81 TOR LEU 82 PHE LEU 75 MET BE 78 TOR VAL 81 THR LEU 82 HIS LEU 75 MET SER 78 THR VAL 81 TOR LEU 82 TYR LEU 75 MET SER 78 ARG VAL 81 TOR LEU 82 PHE LEU 75 MET SER 78 ARG VAL 81 TOR LEU 82 HIS LEU 75 MET BE 78 ARG VAL 81 THR LEU 82 TYR LEU 75 MET BE 78 ASP VAL 81 TOR LEU 82 PHE LEU 75 MET BE 78 ASP VAL 81 TOR LEU 82 HIS LEU 75 MET BE 78 ASP VAL 81 TOR LEU 82 T ? R LEU 75 MET BE 78 GLN VAL 1 TOR LEU 82 PHE LEU 75 MET BE 78 GLN VAL 81 THR LEU 82 HIS LEU 75 MET BE 78 GLN VAL 81 TOR LEU 82 TYR LEU 75 MET BE 78 HIS VAL If THR LEU 82 PHE LEU 75 MET BE 78 HIS VAL SI THR LEU 82 HIS LEU 75 MET BE 78 H1S VAL 81 TOR LEU 82 TYR LEU 75 MET BE 78 LYS VAL 81 TOR LEU 82 PHE LEU 75 MET BE 78 LYS VAL 8 í TOR LEU 82 HIS
LEU 75 MET SER 78 LYS VAL 81 TOR LEU 82 TYR LEU 75 MET SER 78 TYR VAL 81 TOR LEU 82 PHE LEU 75 MET SER 78 TYR VAL 81 TOR LEU 82 HIS LEU 75 MET SER 78 TYR VAL 81 TOR LEU 82 TYR LEU 75 VAL SER 78 ASN VAL 81 TORLEU 82 PHE LEU 75 VAL SER 78 ASN VAL 81 TOR LEU 82 H1S LEU 75 VAL SER 78 ASN VAL 81 TOR LEU 82 TYR LEU 75 VAL SER 7S THR VAL 81 THR LEU 82 PHE LEU 75 VAL SER 78 TOR VAL 81 TOR LEU 82 HIS LEU 75 VAL SER 78 TOR VAL 81 THR LEU 82 TYR LEU 75 VAL SER 78 ARG VAL 81 TOR LEU 82 PHE LEU 75 VAL SER 78 ARG VAL 81 TOR LEU 82 H? S LEU 75 VAL SER 78 ARG VAL 81 THR LEU 82 TYR
LEU 75 VAL SER 78 ASP VAL 81 TOR EU 82 PHE LEU 75 VAL SER 78 ASP VAL 81 TOR LEU 82 HIS LEU 75 VAL SER 78 ASP VAL 81 THR LEU 82 TYR LEU 75 VAL SER 78 GLN VAL 1 TOR LEU 82 PHE LEU 75 VAL SER 78 GLN VAL 81 THR LEU 82 HIS LEU 75 VAL SER 78 GLN VAL 81 TOR LEU 82 TYR LEU 75 VAL SER 78 HIS VAL 81 TOR LEU 82 PHE LEU 75 VAL SER 78 HIS VAL 81 TOR LEU 82 HIS LEU 75 VAL SER 78 HIS VAL 1 TOR LEU 82 T? R LEU 75 VAL SER 78 LYS VAL 81 TOR LEU 82 PHE LEU 75 VAL SER 78 LYS VAL 81 TOR LEU 82 HIS LEU 75 VAL SER 78 LYS VAL 81 TOR LEU 82 TYR
LEU 75 VAL SER 78 TYR VAL SI TO EU 82 PHE LEU 75 VAL SER 78 TYR VAL 81 TOR LEU 82 H? S LEU 75 VAL SER 78 T? R VAL 81 THR LEU 82 TYR LEU 75 HE BE 78 ASN HE 79 LEU LEU 82 PHE LEU 75 ILE BE 78 ASN ILE 79 LEU LEU 82 HIS LEU 75 HE BE 78 ASN? LE 79 LEU LEU 82 TYR LEU 75 WILL BE 78 ASN HE 79 MET LEU 82 PHE LEU 75 HE WILL BE 78 ASN HE 79 MET LEU 82 HIS LEU 75 ILE BE 78 ASN LE 79 MET LEU 82 T? R LEU 75? LE BE 78 ASN ILE 79 THR LEU 82 PHE LEU 75 ILE BE 78 ASN HE 79 TOR LEU 82 HAVE LEU 75 I WILL BE 78 ASN? LE 79 TOR LEU 82 T? R LEU 75 HE BE 78 ASN LE 79 VAL LEU 82 PHE LEU 75 ILE SER 78 ASN HE 79 VAL LEU 82 HIS LEU 75 HE BE 78 ASN HE 79 VAL LEU 82 TYR LEU 75 HE BE 78 THR HE 79 LEU LEU 82 PHE LEU 75 LE BE 78 TOR HE 79 LEU LEU 82 HIS LEU 75? LE BE 78 TOR HE 79 LEU LEU 82 T? R LEU 75 HE BE 78 TOR HE 79 MET LEU 82 PHE LEU 75 ILE BE 78 TOR ILE 79 MET LEU 82 HIS LEU 75 HE BE 78 THR ILE 79 MET LEU 82 TYR LEU 75 HE BE 78 TORILE 79 THR LEU 82 PHE LEU 75 HE BE 78 TOR I LE 79 THR LEU 82 HIS LEU 75 HE BE 78 TOR ILE 79 TOR LEU 82 TYR LEU 75 LE BE 78 TOR HE 79 VAL LEU 82 PHE LEU 75 HE BE 78 THR HE 79 VAL LEU 82 HIS LEU 75 HE BE 78 TOR ILE 79 VAL LEU 82 TYR LEU 75? LE SER 78 ARG HE 79 LEU LEU 82 PHE LEU 75 ILE BE 78 ARG HE 79 LEU LEU 82 HIS LEU 75 WILL BE 78 ARG ILE 79 LEU LEU 82 TYR LEU 75 ILE SER 78 ARG 1LE 79 MET LEU 82 PHE
LEU 75 ILE BE 78 ARG ILE 79 MET LEU 82 HIS LEU 75 HE BE 78 ARG HE 79 MET LEU 82 TYR LEU 75 ILE BE 78 ARG? LE 79 TOR LEU 82 PHE LEU 75 HE BE 78 ARG HE 79 TOR LEU 82 HIS LEU 75 ILE BE 78 ARG HE 79 THR LEU 82 TYR LEU 75 HE BE 78 ARG ILE 79 VAL LEU 82 PHE LEU 75 ILE BE 78 ARG HE 79 VAL LEU 82 HIS LEU 75 HE BE 78 ARG HE 79 VAL LEU 82 TYR LEU 75 ILE BE 78 ASP HE 79 LEU LEU 82 PHE LEU 75? LE SER 78 ASP LE LEU LEU 82 HIS LEU 75 HE BE 78 ASP HE 79 LEU LEU 82 TYR LEU 75 HE BE 78 ASP HE 79 MET LEU 82 PHE LEU 75 HE WILL BE 78 ASP HE 79 MET LEU 82 H? S
LEU 75 HE BE 78 ASP HE 79 MET LEU 82 TYR LEU 75? LE SER 78 ASP HE 79 THR LEU 82 PHE LEU 75 HE BE 78 ASPEL 79 THR LEU 82 H1S. LEU 75? LE BE 78 ASP 1LE 79 THR LEU 82 TYR LEU 75 HE BE 78 ASP ILE 79 VAL LEU 82 PHE LEU 75 HE BE 78 ASP LE 79 VAL LEU 82 HAVE LEU 75? LE SER 78 ASP HE 79 VAL LEU 82 TYR LEU 75 ILE BE 78 GLN HE 79 LEU LEU 82 PHE LEU 75 ILE BE 78 GLN HE 79 LEU LEU 82 H? S LEU 75 ILE BE 78 GLN HE 79 LEU LEU 82 TYR LEU 75 HE BE 78 GLN HE 79 MET LEU 82 PHE LEU 75 HE BE 78 GLN HE 79 MET LEU 82 HIS
LEU 75 HE BE 78 GLN HE 79 MET LEU 82 TYR LEU 75 1LE SER 78 GLN HE 79 THR LEU 82 PHE LEU 75 HE BE 78 GLN HE 79 THR LEU 82 HIS LEU 75 ÍLE SER 78 GLN ÍLE 79 TOR LEU 82 TYR LEU 75 HE BE 78 GLN ÍLE 79 VAL LEU 82 PHE LEU 75 ILE BE 78 GLN ILE 79 VAL LEU 82 HIS LEU 75 HE BE 78 GLN LE 79 VAL LEU 82 TYR LEU 75 HE BE 78 HIS ÍLE 79 LEU LEU 82 PHE LEU 75 ILE BE 78 HIS ILE 79 LEU LEU 82 HIS LEU 75 HE BE 78 H? S ILE 79 LEU LEU 82 TYR LEU 75 HE BE 78 HIS ILE 79 MET LEU 82 PHE LEU 75 HE BE 78 HIS LE 79 MET LEU 82 HIS LEU 75 HE BE 78 HIS LE 79 MET LEU 82 TYR LEU 75 ILE BE 78 HIS ILE 79 THR LEU 82 PHE LEU 75 LE WILL BE 78 HIS LE 79 THR LEU 82 HIS LEU 75 ILE BE 78 HIS LE 79 TOR LEU 82 TYR LEU 75 WILL IT BE 78 HIS? 79 VAL LEU 82 PHE LEU 75 HE BE 78 HIS HE 79 VAL LEU 82 HIS LEU 75 ILE BE 78 H? S ILE 79 VAL LEU 82 TYR LEU 75 WILL BE 78 LYS HE 79 LEU LEU 82 PHE LEU 75? LE BE 78 LYS? LE 79 LEU LEU 82 HIS LEU 75 ILE BE 78 LYS ILE 79 LEU LEU 82 TYR LEU 75 ILE BE 78 LYS ILE 79 MET LEU 82 PHE LEU 75 ITS BE 78 LYS HE 79 MET LEU 82 HIS LEU 75 ILE BE 78 LYS ILE 79 MET LEU 82 TYR LEU 75 HE BE 78 LYS LE 79 THR LEU 82 PHE LEU 75 ILE BE 78 LYS ILE 79 THR LEU 82 H1S LEU 75 ILE BE 78 LYS HE 79 THR LEU 82 T? R LEU 75 ILE SER 78 LYS ILE 79 VAL LEU 82 PHE LEU 75 ILE BE 78 LYS ILE 79 VAL LEU 82 HIS LEU 75 I WILL BE 78 LYS LE 79 VAL LEU 82 TYR LEU 75 I LE BE 78 TYR ILE 79 LEU LEU 82 PHE
LEU 75 HE BE 78 TYR HE 79 LEU LEU 82 HIS LEU 75 ILE BE 78 TYR HE 79 LEU LEU 82 TYR LEU 75 HE BE 78 TYR HE 79 MET LEU 82 PHE LEU 75 HE BE 78 TYR HE 79 MET LEU 82 HIS LEU 75 HE BE 78 T? R HE 79 MET LEU 82 TYR LEU 75 ILE BE 78 T? R ILE 79 THR LEU 82 PHE LEU 75 ILE BE 78 TYR ILE 79 THR LEU 82 HIS LEU 75? LE SER 78 TYR ILE 79 THR LEU 82 TYR LEU 75 ILE SER 78 T? R? LE 79 VAL LEU 82 PHE LEU 75 ILE SER 78 TYR HE 79 VAL LEU 82 H? S LEU 75 HE SER 78 TYR HE 79 VAL LEU 82 TYR LEU 75 MET SER 78 IAN LE 79 LEU LEU 82 PHE LEU 75 MET BE 78 ASN HE 79 LEU LEU 82 HIS
LEU 75 MET BE 78 ASN ILE 79 LEU LEU 82 TYR LEU 75 MET BE 78 ASN ILE 79 MET LEU 82 PHE LEU 75 MET BE 78 ASN HE 79 MET LEU 82 HIS LEU 75 MET BE 78 ASN ILE 79 MET LEU 82 TYR LEU 75 MET BE 78 ASN ILE 79 TOR LEU 82 PHE LEU 75 MET BE 78 ASN ILE 79 THR LEU 82 HIS LEU 7S MET BE 78 ASN ILE 79 TOR LEU 82 TYR LEU 75 MET BE 78 ASN ILE 79 VAL LEU 82 PHE LEU 75 MET BE 78 ASN HE 79 VAL LEU 82 HIS LEU 75 MET BE 78 ASN HE 79 VAL LEU 82 TYR LEU 75 MET BE 78 THR HE 79 LEU LEU 82 PHE LEU 75 MET BE 78 THR ILE 79 LEU LEU 82 H1S
LEU 75 MET BE 78 THR HE 79 LEU LEU 82 TYR LEU 75 MET BE 78 THR ÍLE 79 MET LEU 82 PHE LEU 75 MET BE 78 THR HE 79 MET LEU 82 HIS LEU 75 MET BE 78 THR HE 79 MET LEU 82 TYR LEU 75 MET BE 78 TOR? LE 79 THR LEU 82 PHE LEU 75 MET BE 78 TOR ILE 79 THR LEU 82 HIS LEU 75 MET BE 78 TOR HE 79 TOR LEU 82 T? R LEU 75 MET BE 78 TOR HE 79 VAL LEU 82 PHE LEU 75 MET BE 78 TOR ILE 79 VAL LEU 82 HIS LEU 7 MET BE 78 THR HE -9 VAL LEU 82 TYR LEU 75 MET BE 78 ARG HE 7 LEU LEU 82 PHE LEU 75 MET BE 78 ARG ILE 79 LEU LEU 82 HIS LEU 75 MET BE 78 ARG ILE 79 LEU LEU 82 TYR LEU 75 MET BE 78 ARG HE 79 MET LEU 82 PHE LEU 75 MET BE 78 ARG ILE 79 MET LEU 82 H1S LEU 75 MET BE 78 ARG ILE 79 MET LEU 82 TYR LEU 75 MET BE 78 ARG HE? THR LEU 82 PHE LEU 75 MET BE 78 ARG HE 7 THR LEU 82 H? S LEU 75 MET BE 78 ARG HE 79 THR LEU 82 T? R LEU 75 MET BE 78 ARG HE 79 VAL LEU 82 PHE LEU 75 MET SER 78 ARG LE 79 VAL LEU 82 HIS LEU 75 MET BE 78 ARG ÍLE 79 VAL LEU 82 TYR LEU 75 MET BE 78 ASP HE 79 LEU LEU 82 PHE LEU 75 MET BE 78 ASP ILE 79 LEU LEU 82 HIS LEU 75 MET BE 78 ASP LE 79 LEU LEU 82 TYR LEU 75 MET BE 78 ASP iLE 79 MET LEU 82 PHE LEU 75 MET BE 78 ASP HE 79 MET LEU 82 HIS LEU 75 MET BE 78 ASP HE 79 MET LEU 82 TYR LEU 75 MET BE 78 ASP HE 79 THR LEU 82 PHE LEU 75 MET BE 78 ASP HE 79 TOR LEU 82 HIS LEU 75 MET BE 78 ASP HE 79 THR LEU 82 TYR LEU 75 MET BE 78 ASP ILE 79 VAL LEU 82 PHE
LEU 75 MET BE 78 ASP? LE 79 VAL LEU 82 H? S LEU 75 MET BE 78 ASP? LE 79 VAL LEU 82 TYR LEU 75 MET BE 78 GLN HE 79 LEU LEU 82 PHE LEU 75 MET BE 78 GLN HE 79 LEU LEU 82 HIS LEU 75 MET BE 78 GLN ILE 79 LEU LEU 82 TYR LEU 75 MET SER 78 GLN ILE 79 MET LEU 82 PHE LEU 75 MET SER 78 GLN LE 79 MET LEU 82 HIS LEU 75 MET SER 78 GLN HE 79 MET LEU 82 TYR LEU 75 MET BE 78 GLN HE 79 THR LEU 82 PHE LEU 75 MET BE 78 GLN HE 79 TOR LEU 82 HIS LEU 75 MET BE 78 GLN HE 79 THR LEU 82 TYR LEU 75 MET BE 78 GLN HE 79 VAL LEU 82 PHE
LEU 75 MET BE 78 GLN ILE 79 VAL LEU 82 H? S LEU 75 MET BE 78 GLN ILE 79 VAL LEU 82 TYR LEU 75 MET BE 78 HIS HE 79 LEU LEU 82 PHE LEU 75 MET BE 78 HIS ILE 79 LEU LEU 82 H? S LEU 75 MET BE 78 HIS HE 79 LEU LEU 82 TYR LEU 75 MET BE 78 HIS LE 79 MET LEU 82 PHE LEU 75 MET BE 78 H? S HE 79 MET LEU 82 HIS LEU 75 MET BE 78 H1S HE 79 MET LEU 82 TYR LEU 75 MET BE 78 HIS ILE 79 THR LEU 82 PHE LEU 75 MET BE 78 HIS ILE 79 TOR LEU 82 H? S LEU 75 MET BE 78 HIS HE 79 THR LEU 82 TYR LEU 75 MET BE 78 HIS LE 79 VAL LEU 82 PHE LEU 75 MET BE 78 HIS HE 79 VAL LEU 82 H? S
LEU 75 MET BE 78 HIS HE 79 VAL LEU 82 TYR LEU 75 MET BE 78 LYS? LE 79 LEU LEU 82 PHE LEU 75 MET BE 78 LYS HE 79 LEU LEU 82 HIS LEU 75 MET BE 78 LYS ILE 79 LEU LEU 82 T R LEU 75 MET BE 78 LYS LE 79 MET LEU 82 PHE LEU 75 MET BE 78 LYS LE 79 MET LEU 82 HfS LEU 75 MET BE 78 LYS LE 79 MET LEU 82 TYR LEU 75 MET BE 78 LYS LE 79 THR LEU 82 PHE LEU 75 MET BE 78 LYS? LE "9 THR LEU 82 HIS LEU 75 MET BE 78 LYS LE 79 TOR LEU 82 TYR LEU 75 MET BE 78 LYS LE 79 VAL LEU 82 PHE LEU 75 MET BE 78 LYS? LE 79 VAL LEU 82 H1S LEU 75 MET BE 78 LYS 1LE 79 VAL LEU 82 TYR LEU 75 MET BE 78 T? R ILE 79 LEU LEU 82 PHE LEU 75 MET BE 78 TYR HE 79 LEU LEU 82 HIS LEU 75 MET SER 78 TYR HE 79 LEU LEU 82 TYR LEU 75 MET BE 78 TYR HE 79 MET LEU 82 PHE LEU 75 MET BE 78 TYR ILE 79 MET LEU 82 H? S LEU * 75 MET SER 78 TYR HE 79 MET LEU 82 TYR LEU 75 MET BE 78 TYR LE 79 THR LEU 82 PHE LEU 75 MET BE 78 TYR HE 7 TOR LEU 82 HJS LEU 75 MET BE 78 T? R ILE 79 TOR LEU 82 TYR LEU 75 MET BE 78 TYR HE 79 VAL LEU 82 PHE LEU 75 MET BE 78 TYR ÍLE 79 VAL LEU 82 HiS LEU 75 MET BE 78 TYR HE 79 VAL LEU 82 TYR LEU 75 VAL SER 78 ASN HE 79 LEU LEU 82 PHE LEU 75 VAL SER ASN ÍLE 79 LEU LEU 82 H? S LEU 75 VAL BE 78 ASN HE 79 LEU LEU 82 TYR LEU 75 VAL SER 78 ASN LE 79 MET LEU 82 PHE
LEU 75 VAL SER 78 ASN HE 79 MET LEU 82 HIS LEU 75 VAL SER 78 ASN HE 79 MET LEU 82 TYR LEU 75 VAL SER 78 ASN? LE 79 TOR LEU 82 PHE LEU 75 VAL SER 78 ASN ÍLE 79 TOR LEU 82 HIS LEU 75 VAL SER 78 ASN HE 79 TOR LEU 82 TYR LEU 75 VAL SER 78 ASN ÍLE 79 VAL LEU 82 PHE LEU 75 VAL SER 78 ASN HE 79 VAL LEU 82 HIS LEU 75 VAL SER 78 ASN LE 79 VAL LEU 82 TYR LEU 75 VAL BE 78 TOR HE 79 LEU LEU 82 PHE LEU 75 VAL SER 78 TORILE 79 LEU LEU 82 HIS LEU 75 VAL SER 78 TUR HE 79 LEU LEU 82 TYR LEU 75 VAL SER 78 TOR HE 79 MET LEU 82 PHE LEU 75 VAL SER 78 TOR ILE 79 MET LEU 82 H? S
LEU 75 VAL SER 78 TOR HE 79 MET LEU 82 TYR LEU 75 VAL SER 78 TOR HE 79 TOR LEU yesZ FHE LEU 75 VAL SER 78 TOR HE 79 TOR LEU 82 HIS LEU 75 VAL SER 78 TOR ILE 79 TOR LEU 82 TYR LEU 75 VAL SER 78 THR? LE 79 VAL LEU 82 PHE LEU 75 VAL SER 78 TOR? LE 79 VAL LEU 82 HiS LEU 75 VAL SER 78 TOR HE 79 VAL LEU 82 TYR LEU 75 VAL SER 78 ARG HE 79 LEU LEU 82 PHE LEU 75 VAL SER 78 ARG HE 79 LEU LEU 8 HIS LEU 75 VAL SER 78 ARG HE 79 LEU LEU 82 TYR LEU 75 VAL SER 78 ARG HE 79 MET LEU 82 PHE LEU 75 VAL SER 78 ARG HE 79 MET LEU 82 HIS
LEU 75 VAL SER 78 ARG HE 79 MET LEU 82 TYR LEU 75 VAL SER 78 ARG HE 79 TOR LEU 82 PHE LEU 75 VAL SER 78 ARG ILE 79 TOR LEU 82 HIS LEU 75 VAL SER 78 ARG ILE 79 TOR LEU 82 TYR LEU 75 VAL SER 78 ARG ILE 79 VAL LEU 82 PHE LEU 75 VAL SER 78 ARG HE 79 VAL LEU 82 HIS LEU 75 VAL SER 78 ARG ILE 79 VAL LEU 82 TYR LEU 75 VAL SER 78 ASP ILE 79 LEU LEU 82 PHE LEU 75 VAL BE 78 ASP HE 79 LEU LEU 82 HIS LEU 75 VAL SER 78 ASP LEE 79 LEU LEU 82 TYR LEU 75 VAL SER 'i ASP HE "9 MET LEU 82 PHE LEU 75 VAL SER" 8 ASP? LE 79 MET LEU 82 HIS LEU ? 5 VAL SER 78 ASP? LE 79 MET LEU 82 TY LEU 75 VAL SER 78 ASP HE 79 THR LEU 82 PHE LEU 75 VAL SER 78 ASP HE 79 THR LEU 82 HIS LEU 75 VAL SER 78 ASP ÍLE 79 THR LEU 82 TYR LEU 75 VAL SER 78 ASP LE 79 VAL LEU 82 PHE LEU 75 VAL SER 78 ASP HE 79 VAL LEU 82 HIS LEU 75 VAL SER 78 ASP ILE 79 VAL LEU 82 T? R LEU 75 VAL SER 78 GLN ILE 79 LEU LEU 82 PHE LEU 75 VAL SER 78 GLN? LE 79 LEU LEU 82 HIS LEU 75 VAL SER 78 GLN HE 79 LEU LEU 82 TYR LEU 75 VAL S ER 7S GLN HE 79 MET LEU 12 PHE LEU 75 VAL SER 78 GLN HE 79 MET LEU 82 HIS LEU 75 VAL SER 78 GLN ÍLE 79 MET LEU 82 TYR LEU 75 VAL SER 78 GLN HE 79 THR LEU 82 PHE LEU 75 VAL SER 78 GLN HE 79 THR LEU 82 H? S LEU 75 VAL SER 78 GLN ILE 79 THR LEU 82 TYR LEU 75 VAL SER 78 GLN ILE 79 VAL LEU 82 PHE LEU 75 VAL SER 7g GLN HE VAL LEU 82 H? S LEU 75 VAL SER 7S GLN HE 79 VAL LEU 12 TYR LEU 75 VAL SER 7S HIS HE 79 LEU LEU S2 PHE
LEU 75 VAL SER 78 HIS HE 79 LEU LEU 82 H1S LEU 75 VAL SER 78 HIS HE 79 LEU LEU S2 TYR LEU 75 VAL SER 78 H? S HE 79 MET LEU 82 PHE LEU 75 VAL SER 78 HJS ILE 79 MET LEU 12 HiS LEU 75 VAL SER 78 HIS HE 79 MET LEU 82 TYR LEU 75 VAL SER 78 HIS HE 79 TOR LEU 82 PHE LEU 75 VAL SER 78 HIS HE 79 THR LEU 82 HIS LEU 75 VAL SER 78 HIS HE 79 THR LEU 82 TYR LEU 75 VAL SER 78 H1S HE 79 VAL LEU 82 PHE LEU 75 VAL SER 78 HIS 1LE 79 VAL LEU 82 HIS LEU 75 VAL SER 78 HiS HE 79 VAL LEU 82 TYR LEU 75 VAL SER 7S LYS HE 79 LEU LEU 82 PHE LEU 75 VAL SER 78 LYS HE 79 LEU LEU 82 H3S
LEU 75 VAL SER 78 LYS HE 79 LEU LEU 82 TYR LEU 75 VA SER 7S LYS HE 79 MET LEU 12 PHE LEU 75 VAL SER 78 LYS HE 79 MET LEU 82 H1S LEU 75 VAL SER 78 LYS HE 79 MET LEU 82 TYR LEU 75 VAL SER 78 LYS ILE 79 THR LEU 82 PHE LEU 75 VAL SER 78 LYS HE 79 THR LEU 82 HIS LEU 75 VAL SER 78 LYS HE 79 THR LEU 82 TYR LEU 75 VAL SER 78 LYS HE 79 VAL LEU 82 PHE LEU 75 VAL BE 7S LYS HE 79 VAL LEU 82 HIS LEU 75 VAL BE 78 LYS HE 79 VAL LEU S2 TYR LEU 75 VAL SER 7S TYR HE 79 LEU LEU 82 PHE LEU 75 VAL SER 78 TYR HE 79 LEU LEU 82 HIS
LEU 75 VAL SER 78 TYR HE 79 LEU LEU 82 TYR LEU 75 VAL SER 78 TYR HE 79 MET LEU 82 PHE LEU 75 VAL SER 78 TYR HE 7 MET LEU 82 H? S LEU 75 VAL SER 78 TYR HE 79 MET LEU 82 TYR LEU 75 VAL SER 78 TYR HE 79 THR LEU 82 PHE LEU 75 VAL SER 78 TYR HE 79 TOR LEU 82 HIS LEU 75 VAL SER 78 TYR HE 79 TOR LEU 82 T? R LEU 75 VAL SER 78 TYR HE 79 VAL LEU 82 PHE LEU 75 VAL SER 78 TYR HE 79 VAL LEU S2 HIS LEU "5 VAL SER 78 TYR HE 79 VAL LEU 82 TYR LEU 75 HE BE" 8 ASN HE 79 LEU VAL 81 THR LEU 75 LE BE 78 ASN LE 79 MET VAL 81 THR LEU 75 HE BE 78 ASN HE 79 THR VAL 81 TOR LEU 75 HE BE 78 ASN HE 79 VAL VAL 81 TOR LEU 75 ILE BE 78 THR ILE 79 LEU VAL 81 TOR LEU 75 HE BE 78 TOR HE 79 MET VAL 81 THR LEU 75 HE BE 78 THR HE 79 THR VAL 81 TOR LEU 75 HE BE 78 THR HE 79 VAL VAL 81 TOR LEU 75 HE BE 78 ARG HE 79 LEU VAL 81 TOR LEU 75? LE SER 78 ARG HE 79 MET VAL 81 TOR LEU 75 HE BE 78 ARG ÍLE 79 TOR VAL 81 TOR LEU 75 HE BE 78 ARG LE 79 VAL VAL 81 TOR LEU 75 HE BE 78 ASP HE 79 LEU VAL 81 TOR LEU 75 HE BE 78 ASP ILE 79 MET VAL 81 THR LEU 75 HE BE 78 ASP HE 79 THR VAL 81 THR LEU 75 HE BE 78 ASP HE 79 VAL VAL 81 THR LEU 75 HE SER 78 GLN HE 79 LEU VAL 81 THR LEU 75 HE BE 78 GLN ÍLE 79 MET VAL 81 THR
LEU 75 HE BE 78 GLN HE 79 THR VAL 81 TOR LEU 75 HE BE 78 GLN? LE 79 VAL VAL 81 THR LEU 75 HE BE 78 HIS ILE 79 LEU VAL 81 TOR LEU 75 HE BE 78 HIS LE 79 MET VAL 8 i THR LEU 75 HE BE 78 HiS ILE 79 THR VAL 1 TOR LEU 75 HE BE 7 HIS HE 79 VAL VAL 81 TOR LEU 75 HE BE 78 LYS HE 79 LEU VAL 81 TOR LEU 75 HE BE 78 LYS HE 79 MET VAL 81 TOR LEU 75 ILE BE 78 LYS ILE 79 THR VAL 81 TOR LEU 75 HE BE 78 LYS ILE 79 VAL VAL 81 TOR LEU 75 HE BE 78 TYR ILE 79 LEU VAL 81 TOR LEU 75 HE BE 78 TYR HE 79 MET VAL 81 TOR LEU 75 HE WILL BE 78 TYR HE 79 TOR VAL 81 TOR
LEU 75 HE BE 78 TYR HE 79 VAL VAL 81 TOR LEU 75 MET BE 78 ASN HE 79 LEU VAL 81 TOR LEU 75 MET BE 78 ASN HE 79 MET VAL 81 THR LEU 75 MET BE 78 ASN HE 79 TOR VAL 81 TOR LEU 75 MET BE 78 ASN HE 79 VAL VAL 1 TOR LEU 75 MET BE 78 TOR ILE 79 LEU VAL 81 TOR LEU 75 MET BE 78 TOR ILE 79 MET VAL 81 THR LEU 75 MET BE 78 TOR HE 79 THR VAL 1 THR LEU 75 MET BE 78 THR HE 79 VAL VAL 1 THR LEU 75 MET BE 78 ARG HE 79 LEU VAL 81 THR LEU 75 MET BE 78 ARG HE 79 MET VAL 81 TOR LEU 75 MET BE 78 ARG HE 79 THR VAL 81 THR
LEU 75 MET BE 78 ARG HE 79 VAL VAL 81 TOR LEU 75 MET BE 78 ASP ILE 79 LEU VAL 81 TOR LEU 75 MET BE 78 ASP HE 79 MET VAL 81 THR LEU 75 MET BE 78 ASP ILE 79 THR VAL 81 THR LEU 75 MET BE 78 ASP HE 79 VAL VAL 81 THR LEU 75 ET SER 78 GLN HE 79 LEU VAL 81 THR LEU 75 MET BE 78 GLN? LE 79 MET VAL 81 THR LEU 75 MET SER 78 GLN HE 79 THR VAL 81 TOR LEU 75 MET BE 78 GLN HE 79 VAL VAL 81 TOR LEU 75 MET BE 78 HIS LE 79 LEU VAL 1 TOR LEU 75 MET BE 78 HiS HE 79 MET VAL 81 THR LEU 75 MET BE 78 HIS ILE 79 THR VAL 81 THR LEU 75. MET BE "8 HIS HE 79 VAL VAL SI THR LEU 75 MET BE 78 LYS HE 79 LEU VAL 81 THR LEU 75 MET BE 78 LYS HE 79 MET VAL 8 i THR LEU 75 MET BE 78 LYS HE 79 THR VAL 81 TOR LEU 75 MET BE 78 LYS HE 79 VAL VAL 1 THR LEU 75 MET BE 78 TYR HE 79 LEU VAL 81 TOR LEU 75 MET BE 78 TYR ILE 79 MET VAL 81 TOR LEU 75 MET BE 78 TYR HE 79 TOR VAL 81 TOR LEU 75 MET SER 78 TYR HE 79 VAL VAL 81 THR LEU 75 VAL SER 78 ASN HE 79 LEU VAL 81 TOR LEU 75 VAL SER 78 ASN HE 79 MET VAL 81 THR LEU 75 VAL SER 78 ASN? LE 79 THR VAL 81 THR LEU 75 VAL SER 78 ASN ILE 79 VAL VAL 81 THR LEU 75 VAL SER 78 THR ILE 79 LEU VAL 81 TOR LEU 75 VAL SER 78 TOR ÍLE 79 MET VAL 81 THR LEU 75 VAL SER 78 TOR LE 79 THR VAL 8 THR LEU 75 VAL SER 78 THR HE 79 VAL VAL 81 THR LEU 75 VAL SER 78 ARG ILE 79 LEU VAL 81 TOR LEU 75 VAL SER 78 ARG HE 79 ET VAL 81 THR
LEU 75 VAL SER 78 ARG ILE 79 TOR VAL 81 TOR LEU 75 VAL SER 78 ARG HE 79 VAL VAL 81 THR LEU 75 VAL SER 78 ASP? LE 79 LEU VAL 81 THR LEU 75 VAL SER 78 ASP ILE 79 MET VAL 81 THR LEU 75 VAL BE 78 ASP HE 79 TOR VAL 81 THR LEU 75 VAL SER 78 ASP HE 79 VAL VAL 81 TOR LEU 75 VAL SER 78 GLN HE 79 LEU VAL 81 TOR LEU 75 VAL SER 78 GLN LE 79 MET VAL 1 THR LEU 75 VAL SER 78 GLN ILE 79 TOR VAL 81 TOR LEU 75 VAL SER 78 GLN HE 79 VAL VAL 81 THR LEU 75 VAL SER 78 H1S? LE 79 LEU VAL 81 TOR LEU 75 VAL SER 78 HIS HE 79 MET VAL 81 TOR LEU 75 VAL SER 78 HIS HE 79 TOR VAL 81 TOR
LEU 75 VAL SER 78 H? S ILE 79 VAL VAL 81 TOR LEU 75 VAL SER 78 LYS HE 79 LEU VAL 81 THR LEU 75 VAL SER 78 LYS ILE 79 MET VAL 81 TOR LEU 75 VAL SER 78 LYS HE 79 TOR VAL 81 TOR LEU 75 VAL SER 78 LYS ILE 79 VAL VAL 81 TOR LEU 75 VAL SER 78 TYR HE 79 LEU VAL 81 TOR LEU 75 VAL SER 78 TYR HE 79 MET VAL 81 TOR LEU 75 VAL SER 78 TYR HE 7 TOR VAL 81 THR LEU 75 VAL SER 78 TYR HE 79 VAL VAL 81 TOR LEU 75 ILE ASN 76 HIS VAL 81 TOR LEU 82 PHE LEU 75 HE ASN 76 HIS VAL 81 THR LEU 82 HIS LEU 75 HE ASN 76 H1S VAL 81 TOR LEU 82 TYR
LEU 75 aMET ASN 7 HIS VAL 81 TOR LEU 82 PHE LEU 75 MET ASN 76 H1S VAL 81 TOR LEU 82 H? S LEU 75 MET ASN 76 HIS VAL 81 THR LEU 82 TYR LEU 75 VAL ASN 7 HIS VAL 81 TOR LEU 82 PHE LEU 75 VAL ASN 76 HIS VAL 81 THR LEU 82 HIS LEU 75 VAL ASN 76 HIS VAL 81 TOR LEU 82 TYR LEU 75 iLE ASN 76 HSS LE 79 LEU LEU 82 PHE LEU 75 ILE ASN 76 HIS HE 79 LEU LEU 82 HIS LEU 75 ILE ASN 76 HIS HE 79 LEU LEU 82 T? R LEU 75 ¡LE ASN 76 HIS ILE 79 MET LEU 82 PHE LEU 75 ÍLE ASN 76 H? S HE 79 MET LEU 82 H1S LEU 75 ILE ASN 7 HIS HE 79 MET LEU 82 T? R LEU 75 HE ASN 76 H¡S SER 78 GLN LEU 82 TYR LEU 75 LE ASN 76 H? S BE 78 HIS LEU 82 PHE LEU 75 HE ASN 76 HIS BE 78 HIS LEU 82 HIS LEU 75 HE ASN 76 HIS BE 78 H¡S LEU 82 TYR LEU 75 HE ASN 76 HIS BE 78 LYS LEU 82 PHE LEU 75 LE ASN 76 HIS BE 78 LYS LEU .82 HIS LEU 75 ILE ASN 76 HIS BE 78 LYS LEU 82 TYR LEU 75 LE ASN 76 HIS BE 78 TYR LEU 82 PHE LEU 75 ILE ASN 76 H? S BE 78 TYR LEU 82 HIS LEU 75? LE ASN 76 HIS BE 78 TYR LEU 82 T? R LEU 75 MET ASN 76 HIS BE 78 ASN LEU 82 PHE LEU 75 MET ASN 76 H? S BE 78 ASN LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 ASN LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 TOR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 THR LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 TOR LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 ARG LEU 82 PHE LEU 75 MET ASN 76 H? S SER 78 ARG LEU 82 HIS LEU 75 MET ASN 76 H? S SER 78 ARG LEU 82 TYR LEU 75 MET ASN 76 HIS BE 78 ASP LEU 82 PHE
LEU 75 MET ASN 76 HIS BE 78 ASP LEU 82 HIS LEU 75 MET ASN 76 HIS BE 78 ASP LEU 82 T? R LEU 75 MET ASN 76 HIS SER 78 GLN LEU 82 PHE LEU 75 MET ASN 76 H1S SER 78 GLN LEU 82 HIS LEU 75 MET ASN 76 HIS BE 78 GLN LEU 82 TYR LEU 75 MET ASN 76 HIS BE 78 HIS LEU 82 PHE LEU 75 MET ASN 76 HIS BE 78 HIS LEU 82 HIS LEU 75 MET ASN 76 HIS BE 78 HIS LEU 82 TYR LEU 75 MET ASN 76 HIS BE 78 LYS LEU 82 PHE LEU 75 MET ASN 76 HIS BE 78 LYS LEU 82 HIS LEU 75, ET ASN 76 HIS BE 78 LYS LEU 82 TYR LEU 75 MET ASN 76 HIS BE 78 TYR LEU 82 PHE
LEU 75 MET ASN 76 HIS BE 78 T? R LEU 82 HIS LEU 75 MET ASN 76 H? S BE 78 TYR LEU 82 TYR LEU 75 VAL ASN 76 HIS BE 78 ASN LEU 82 PHE LEU 75 VAL ASN 76 HIS BE 78 ASN LEU 82 H? S LEU 75 VAL ASN 76 HIS SER 78 ASN LEU 82 TYR LEU 75 VAL ASN 76 H? S SER 78 TOR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 TOR LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 TOR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 ARG LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 ARG LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 ARG LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 ASP LEU 82 PHE LEU 75 VAL ASN 76 HIS BE 78 ASP LEU 82 HIS
LEU 75 VAL ASN 76 HIS SER 78 ASP LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 GLN LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 GLN LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 GLN LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 HIS LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 HIS LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 HiS LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 LYS LEU 82 PHE LEU 75 VAL ASN 76 HIS BE 78 LYS LEU 82 HIS LEU 75 VAL ASN 76 HIS BE 78 LYS LEU 82 TYR LEU 75 VAL ASN 76 HIS BE 78 TYR LEU 82 PHE LEU 75 LE ASN 76 HIS BE 78 GLN LEU 82 TYR LEU 75 LE ASN 6 HIS BE 78 HIS LEU 82 PHE LEU 75 LE ASN 76 H¡S BE 78 H1S LEU 82 HIS LEU 75? LE ASN 76 HIS BE 78 HIS LEU 82 TYR LEU 75 ILE ASN 76 H1S BE 78 LYS LEU 82 PHE LEU 75 ¡LE ASN 76 H¡S BE 78 LYS LEU 82 HIS LEU 75 ÍLE ASN 76 HIS BE 78 LYS LEU 82 TYR LEU 75 ILE ASN 76 HIS BE 78 TYR LEU 82 PHE LEU 75 ILE ASN 76 HIS BE 78 TYR LEU 82 HiS LEU 75 HE ASN 76 HIS BE 78 T? R LEU 82 T? R LEU 75 MET ASN 76 HIS BE 78 ASN LEU 82 PHE L EU 75 MET ASN 76 HIS BE 78 ASN LEU 82 H? S LEU 75 MET ASN 76 HIS BE 78 ASN LEU 82 T? R LEU 75 MET ASN 76 H? S BE 78 TOR LEU 82 PHE LEU 75 MET ASN 76 HIS BE 78 THR LEU 82 HIS LEU 75 MET ASN 76 HIS BE 78 TOR LEU 82 TYR LEU 75 MET ASN 76 HIS BE 78 ARG LEU 82 PHE LEU 75 MET ASN 76 HIS BE 78 ARG LEU 82 HIS
LEU 75 MET ASN 76 HIS BE 78 ARG LEU 82 TYR LEU 75 MET ASN 76 HIS BE 78 ASP LEU 82 PHE LEU 75 MET ASN 76 H1S BE 78 ASP LEU 82 HIS LEU 75 MET ASN 76 HIS BE 78 ASP LEU 82 T? R LEU 75 MET ASN 76 HIS SER 78 GLN LEU 82 PHE LEU 75 MET ASN 76 H? S SER 78 GLN LEU 82 H? S LEU 75 MET ASN 76 HIS SER 78 GLN LEU 82 TYR LEU 75 MET ASN 76 HIS BE 78 HIS LEU 82 PHE LEU 75 MET ASN 76 HIS BE 78 HIS LEU 82 HIS LEU 75 MET ASN 76 HIS BE 78 H? S LEU 82 TYR LEU 75 MET ASN 76 HIS BE 78 LYS LEU 82 PHE LEU 75 MET ASN 76 HIS BE 78 LYS LEU 82 HIS LEU 75 MET ASN 76 HIS BE 78 LYS LEU 82 TYR
LEU 75 MET ASN 76 HIS SER 78 TYR LEU 82 PHE LEU 75 MET ASN 76 H1S SER 78 TYR LEU 82 HIS LEU 75 MET ASN 76 HIS BE 78 TYR LEU 82 T? R LEU 75 VAL ASN 76 H? S SER 78 ASN LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 ASN LEU 82 H1S LEU 75 VAL ASN 76 HIS SER 78 ASN LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 THR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 TOR LEU 82 H1S LEU 75 VAL ASN 76 HIS BE 78 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS BE 78 ARG LEU 82 PHE LEU 75 VAL ASN 76 HIS BE 78 ARG LEU 82 HIS LEU 75 VAL ASN 76 HIS BE 78 ARG LEU 82 TYR
LEU 75 VAL ASN 76 H1S SER 78 ASP LEU 82 PHE LEU 75 VAL ASN 76 H1S SER 78 ASP LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 ASP LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 GLN LEU 82 PHE LEU 75 VAL ASN 76 HIS BE 78 GLN LEU 82 HIS LEU 75 VAL ASN 76 HIS BE 78 GLN LEU 82 TYR LEU 75 VAL ASN 76 HIS BE 78 HIS LEU 82 PHE LEU 75 VAL ASN 76 H? S BE 78 H1S LEU 82 H? S LEU 75 VAL ASN 76 HERE TO BE 78 HIS LEU 82 TYR LEU 75 VAL ASN 76 HIS BE 78 LYS LEU 82 PHE LEU 75 VAL ASN 76 H1S BE 78 LYS LEU 82 HIS LEU 75 VAL ASN 76 HIS BE 78 LYS LEU 82 TYR LEU 75 VAL ASN 76 HIS BE 78 T? R LEU 82 PHE LEU 75 VAL ASN 76 H1S SER 78 TYR LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 TYR LEU 82 TYR LEU 75 HE ASN 76 HiS SER 78 ASN VAL 8! TOR LEU 75 LE ASN 76 HiS SER 78 THR VAL 81 TOR LEU 75 HE ASN 76 HIS SER 78 ARG VAL 81 THR LEU 75 LE ASN 76 H1S SER 78 ASP VAL 81 THR LEU 75? LE ASN 76 HIS SER 78 GLN VAL 81 TOR LEU 75 HE ASN 76 HIS BE 78 HIS VAL 81 THR LEU 75 HE ASN 76 HIS BE 78 LYS VAL 81 TOR LEU 75 HE ASN 76 H1S SER 78 TYR VAL 81 TOR LEU 75 MET ASN 76 HIS SER 78 ASN VAL 81 TOR LEU 75 MET ASN 76 HIS SER 78 THR VAL 81 THR LEU 75 MET ASN 76 H¡S SER 78 ARG VAL 81 THR LEU 75 MET ASN 76 H1S SER 78 ASP VAL 81 THR LEU 75 MET ASN 76 HIS SER 78 GLN VAL 81 THR LEU 75 MET ASN 76 H? S BE 78 HIS VAL 81 THR LEU 75 MET ASN 76 HIS BE 78 LYS VAL 81 THR LEU 75 MET ASN 76 HIS BE 78 TYR VAL 81 TOR LEU 75 VAL ASN 76 HIS BE 78 ASN VAL 81 TOR
LEU 75 VAL ASN 76 HiS SER 78 TOR VAL 81 TOR LEU 75 VAL ASN 76 HIS SER 78 ARG VAL 8 J THR LEU 75 VAL ASN 7 HIS SER 78 ASP VAL 81 THR LEU 75 VAL ASN 76 HIS SER 78 GLN VAL 81 THR LEU 75 VAL ASN 76 HIS SER 78 HIS VAL 81 TOR LEU 75 VAL ASN 76 HIS SER 78 LYS VAL 81 TOR LEU 75 VAL ASN 76 HIS SER 78 TYR VAL 81 TOR LEU 75 HE ASN 76 HIS SER 78 ASN ILE 79 LEU LEU 75 HE ASN 76 HIS BE 78 ASN ILE 79 MET LEU 75 HE ASN 76 HIS SER 78 ASN ÍLE 79 TOR LEU 75 HE ASN 76 HiS SER 78 ASN HE 79 VAL LEU 75 HE ASN 76 HiS SER 78 TOR HE 79 LEU
LEU 75 HE ASN 76 HIS BE 78 THR ÍLE 79 MET LEU 75 ILE ASN 76 HIS BE 78 TOR ILE 79 THR LEU 75 ILE ASN 76 HIS BE 78 TOR HE 79 VAL LEU 75 HE ASN 76 HIS BE 78 ARG ÍLE 79 LEU LEU 75 HE ASN 76 HIS BE 78 ARG ILE 79 MET LEU 75 HE ASN 76 H? S BE 78 ARG? LE 79 TOR LEU 75 HE ASN 76 HiS BE 78 ARG? LE 79 VAL LEU 75 ILE ASN 76 HIS BE 78 ASP LE 79 LEU LEE 75 ILE ASN 76 HIS BE 78 ASP HE 79 MET LEU 75 ILE ASN 76 H? S BE 78 ASP? LE 79 TOR LEU 75? LE ASN 76 HIS BE 78 ASP? LE 79 VAL LEU 75? LE ASN 76 H1S BE 78 GLN ILE 79 LEU LEU 75? LE ASN 76 HIS BE 78 GLN ILE 79 MET
LEU 75 ILE ASN 76 HIS BE 78 GLN LE 79 THR LEU 75 HE ASN 76 HIS BE 78 GLN ILE 79 VAL LEU 75 HE ASN 76 HIS BE 78 HIS HE 79 LEU LEU 75 HE ASN 76 HiS BE 78 H? S ÍLE 79 MET LEU 75 HE ASN 76 HIS BE 78 HiS LE 79 THR LEU 75 LE ASN 76 HIS BE 78 HIS ILE 79 VAL LEU 75 ILE ASN 76 H? S BE 78 LYS ÍLE 79 LEU LEU 75 HE ASN 76 HIS BE 78 LYS HE 79 MET LEU 75 1LE ASN 76 H1S BE 78 LYS HE 79 THR LEU 75 HE ASN 76 H1S BE 78 LYS HE 79 VAL LEU 75 ÍLE ASN 76 H? S BE 78 TYR HE 79 LEU LEU 75 HE ASN 7 HIS BE 78 TYR HE 79 MET LEU 75 ILE ASN "6 HIS SER 78 TYR HE" 9 TOR LEU 75 ILE ASN 6 HIS SER 78 TYR 1LE 79 VAL LEU 75 MET ASN 76 HiS SER 78 ASN ILE 79 LEU- LEU 75 MET ASN 76 H1S SER 78 ASN HE 79 MET LEU 75 MET ASN 76 HIS BE 78 ASN ILE 79 THR LEU 75 MET ASN 76 HIS BE 78 ASN LE 79 VAL LEU 75 MET ASN 76 HIS BE 78 THR HE 79 LEU LEU 75 MET ASN 76 HIS BE 78 TOR HE 79 MET LEU 75 MET ASN 76 HIS BE 78 THR HE 79 THR LEU 75 MET ASN 76 HIS BE 78 TOR ILE 79 VAL LEU 75 MET ASN 76 H ÍS BE 78 ARG HE 79 LEU LEU 75 MET ASN 76 HIS BE 78 ARG HE 79 MET LEU 75 iMET ASN 76 HIS BE 78 ARG LE 79 TOR LEU 75 MET ASN 76 HIS BE 78 ARG LE 79 VAL LEU 75 MET ASN 76 HIS BE 78 ASP LE 79 LEU LE 75 MET ASN 76 HIS BE 78 ASP LE 79 MET LEU 75 MET ASN 76 HIS BE 78 ASP HE 79 TOR LEU 75 MET ASN 76 HIS BE 78 ASP? LE 79 VAL LEU 75 MET ASN 76 H¡S SER 78 GLN HE 79 LEU
LEU 75 MET ASN 76 H? S BE 78 GLN LE 79 MET LEU 75 MET ASN 76 H¡5 SER 78 GLN LE 79 TOR LEU 75 MET ASN 76 HIS SER 78 GLN ILE 79 VAL LEU 75 MET ASN 76 HIS SER 78 HIS HE 79 LEU LEU 75 MET ASN 76 H? S BE 78 HIS ILE 9 MET LEU 75 MET ASN 76 HIS BE 78 H? S ILE 79 THR LEU 75 MET ASN 76 HIS BE 78 HIS ILE 79 VAL LEU 75 MET ASN 76 HIS BE 78 LYS HE 79 LEU LEU 75 MET ASN 76 HIS BE 78 LYS 1LE 79 MET LEU 75 MET ASN 76 HIS BE 78 LYS LE 79 THR LEU 75 MET ASN 76 H1S BE 78 LYS LE 79 VAL LEU 75 MET ASN 76 HIS BE 78 TYR LE 79 LEU LE 75 MET ASN 76 HIS BE 78 TYR HE 79 MET
LEU 75 MET ASN 76 HIS BE 78 TYR? LE 79 TOR LEU 75 MET ASN 76 HIS BE 78 TYR ILE 79 VAL LEU 75 VAL ASN 76 HIS SER 78 ASN LE 79 LEU LEU 75 VAL ASN 76 HIS SER 78 ASN LE 79 MET LEU 75 VAL ASN 76 HIS SER 78 ASN HE 79 THR LEU 75 VAL ASN 76 HIS SER 78 ASN LE 79 VAL LEU 75 VAL ASN 76 HIS SER 78 THR ILE 79 LEU LEU 75 VAL ASN 76 HIS SER 78 TOR ÍLE 79 MET LEU 75 VAL ASN 76 HJS SER 78 THR HE 79 TOR LEU 75 VAL ASN 76 HiS SER 78 THR ILE 79 VAL LEU 75 VAL ASN 76 HIS SER 78 ARG LE 79 LEU LEU 75 VAL ASN 76 HIS SER 78 ARG ILE 79 MET
LEU 75 VAL ASN 76 HIS BE 78 ARG LE 79 THR LEU 75 VAL ASN 76 HIS BE 78 ARG ILE 79 VAL LEU 75 VAL ASN 76 H? S BE 78 ASP LE 79 LEU LEU 75 VAL ASN 76 HIS BE 78 ASP ? LE 79 MET LEU 75 VAL ASN 76 HIS SER 78 ASP ILE 79 TOR LEU 75 VAL ASN 76 HIS SER 78 ASPEL 79 VAL LEU 75 VAL ASN 76 HIS SER 78 GLN ILE 79 LEU LEU 75 VAL ASN 76 HIS SER 78 GLNILE 79 MET LEU 75 VAL ASN 76 H1S SER 78 GLN ÍLE 79 TOR LEU 75 VAL ASN 76 HIS SER 78 GLN LE 79 VAL LEU 75 VAL ASN 76 HIS BE 78 HIS ILE 79 LEU LEU 75 VAL ASN 76 HIS BE 78 HIS ÍLE 79 MET LEU 5 VAL ASN 76 HIS BE 78 HtS LE "9 THR LEU 75 VAL ASN 76 HIS BE 78 H1S LE" 9 VAL LEU 75 VAL ASN 76 HIS BE 78 LYS ILE 79 LEU LEU 75 VAL ASN 76 HIS BE 78 LYS HE 79 MET LEU 75 VAL ASN 76 HIS BE 78 LYS LE 79 THR LEU 75 VAL ASN 76 HIS BE 78 LYS ILE 79 VAL LEU 75 VAL ASN 76 HIS BE 78 TYR ILE 79 LEU LEU 75 VAL ASN 76 HIS BE 78 TYR HE 79 MET LEU 75 VAL ASN 76 HIS SER 78 TYR HE 79 THR LEU 75 VAL ASN 76 HIS SER 78 TYR ILE 79 VAL TABLE 6 Five-fold substitution variants ASN 76 HIS SER 78 ASN ÍLE 79 LEU VAL 81 THR LEU 82 PHE ASN 76 HIS SER 78 ASN ILE 79 LEU VAL 1 THR LEU 82 HIS ASN 76HISSER 78 ASN HE 79 LEU VAL 81 THRLEU 82 TYR ASN 76 HIS SER 78 ASN ILE 79 MET VAL 1 THR LEU 82 PHE ASN 76 HIS SER 78 ASN iLE 79 MET VAL 81 THR LEU 82 H? S ASN 7 HISSER 78 ASN? LE 79 MET VAL 81 THRLEU 82 TYR ASN 7 6 HIS BE 78 ASN HE 79 THR VAL 81 THR LEU 82 PHE
ASN 76 HIS BE 78 ASN ILE 79 THR VAL 81 THR LEU 82 HIS ASN 76HISSER 78 ASN HE 79 THR VAL 81 THRLEU 82 TYR ASN 76HISSER 78 ASN HE 79 VAL VAL 81 THRLEU 82 PHE ASN 76 HIS SER 78 ASN ILE 79 VAL VAL 81 THR LEU 82 HIS ASN 76 HIS BE 78 ASN ILE 79 VAL VAL 81 THR LEU 82 TYR ASN 7 HISSER 78 THR HE 79 LEU VAL 81 THRLEU 82 PHE ASN 76H1SSER 78 THR HE 79 LEU VAL 81 THRLEU 82 HIS ASN 76 H1S SER 78 THR? LE 79 LEU VAL 81 THR LEU 82 TYR ASN 76 H? S SER 78 THR HE 79 MET VAL 81 TH LEU 82 PHE ASN 76HISSER 78 THR HE 79 MET VAL 81 THRLEU 82 HIS ASN 76HISSER 78 THR HE 79 MET VAL 81 THRLEU 82 TYR ASN 76HISSER 78 THR HE 79 THR VAL 81 THRLEU 82 PHE
ASN 76HISSER 78 THR HE 79 THR VAL 81 THRLEU 82 HIS ASN 76HISSER 78 THR HE 79 THR VAL 81 THR LEU 82 TYR ASN 76HISSER 78 THR HE 79 VAL VAL 81 THRLEU 82 PHE ASN 76 HIS SER 78 THR ILE 79 VAL VAL 81 THR LEU 82 HIS ASN 76HISSER 78 THR HE 79 VAL VAL 81 THRLEU 82 TYR ASN 76 HIS SER 78 ARG ILE 79 LEU VAL 1 THR LEU 82 PHE ASN 76 HIS SER 78 ARG ILE 79 LEU VAL 81 THR LEU 82 HIS ASN 76 H1S SER 78 ARG ÍLE 79 LEU VAL 81 THR LEU 82 TYR ASN 76 HIS BE 78 ARG HE 79 MET VAL 81 THR LEU 82 PHE ASN 76 HIS SER 78 ARG ILE 79 MET VAL 81 THR LEU 82 HIS ASN 76HISSER 78 ARG HE 79 MET VAL 81 THRLEU 82TYR ASN 76HISSER 78 ARG HE 79 THR VAL 81 THRLEU 82 PHE
ASN 76 H1S SER 78 ARG HE 79 THR VAL 8 i THR LEU 82 HIS ASN 76 HIS BE 78 ARG HE 79 THR VAL 81 THR LEU 82 TYR ASN 76HISSER 78 ARG HE 79 VAL VAL 81 THRLEU 82 PHE ASN 76 HIS SER 78 ARG HE 79 VAL VAL 81 THR LEU 82 HIS ASN 76 HIS SER 78 ARG ILE 79 VAL VAL 81 THR LEU 82 TYR ASN 76 H1S SER 78 ASP ILE 79 LEU VAL 81 THR LEU 82 PHE ASN 76 HIS SER 78 ASP 1LE 79 LEU VAL 81 THR LEU 82 HIS ASN 76HISSER 78 ASP HE 79 LEU VAL 81 THRLEU 82 TYR ASN 76HISSER 78 ASP HE 79 MET VAL 81 THRLEU 82 PHE ASN 76 HIS SER 78 ASP ILE 79 MET VAL 81 THR LEU 82 HIS SN 76 HIS SER 78 ASP LE 79 MET VAL 81 THR LEU 82 TYR SN 76 HIS BE 78 ASP LE 79 THR VAL 81 THRLEU 82 PHE ASN 76 HIS BE 78 ASP HE 79 TOR VAL 81 THR LEU 82 HIS SN 76 H1S SER 78 ASP LE 79 THR VAL 81 TORLEU 82TYR SN 76 H¡S BE 78 ASP LE 79 VAL VAL 81 THRLEU 82 PHE SN 76 HIS BE 78 ASP LE 79 VAL VAL 81 TORLEU 82H1S SN 76 H? S SER 78 ASP HE 79 VAL VAL 81 THRLEU 82 TYR SN 76 HiS SER 78 GLN LE 79 LEU VAL 81 THR LEU 82 PHE SN 76HISSER 78 GLN HE 79 LEU VAL 81 TORLEU 82 HIS SN 76 H1S SER 78 GLN LE 79 LEU VAL 81 TOR LEU 82 TYR SN 76 HIS SER 78 GLN HE 79 MET VAL 81 THR LEU 82 PHE SN 76 HIS SER 78 GLN LE 79 MET VAL 8 i TOR LEU 82 HIS SN 76 H? S SER 78 GLN ILE 79 MET VAL 81 THR LEU 82 TYR SN 76 H? S SER 78 GLN LE 79 THR VAL 81 TOR LEU 82 PHE SN 76 HIS SER 78 GLN ÍLE 79 THR VAL 81 TOR LEU 82 HIS SN 76 HIS BE 78 GLN LE 79 THR VAL 81 THRLEU 82 TYR SN 76 HIS SER 78 GLN LE 79 VAL VAL 8! TORLEU 82 PHE SN 76H¡SSER 78 GLN LE 79 VAL VAL 81 TORLEU 82HIS SN 76 HIS BE 78 GLN LE 79 VAL VAL 81 THR LEU 82 TYR ASN 76 H? S BE 78HÍSILE 79 LEU VAL 81 TORLEU 82 PHE
ASN 76 HIS'SER 78 HIS HE 79 LEU VAL 81 TORLEU 82 HIS ASN 76 HIS BE 78 H1S 1LE 79 LEU VAL 1 TOR LEU 82 T? R SN 76 HIS BE 78 H1S? LE 79 MET VAL 81 THR LEU 82 PHE ASN 76 H? S BE 78 HIS HE 79 MET VAL 81 THR LEU 82 HIS SN 76 HIS BE 78 HIS LE 79 MET VAL 81 THR LEU 82 TYR ASN 76 HIS BE 78 HIS LE 79 TOR VAL 81 TOR LEU 82 PHE ASN 7 HISSER 78 HIS HE 79 TUR VAL 81 THRLEU 82 HIS SN 76HISSER 78 H1S HE 79 THR VAL 81 THR LEU 82 TYR ASN 76HISSER 78HISHE 79 VAL VAL 81 THRLEU 82 PHE ASN 76 H? S SER 78 HIS 1LE 79 VAL VAL 81 THR LEU 82 HIS SN 76 HIS BE 78 HIS ILE 79 VAL VAL 81 TOR LEU 82 TYR SN 76 HIS BE 78 LYS HE 79 LEU VAL 81 TOR LEU 82 PHE ASN 76 HiS SER 78 LYS LE 79 LEU VAL 81 THR LEU 82 HIS SN 76 HIS SER 78 LYS HE 79 LEU VAL 81 TOR LEU 82 TYR SN 76 H1S SER 78 LYS LE 79 MET VAL 81 TOR LEU 82 PHE ASN 76 HIS SER 78 LYS ILE 79 MET VAL 81 THR LEU 82 H1S SN 76 HIS SER 78 LYS ILE 79 MET VAL 81 THR LEU 82 TYR SN 76 HIS BE 78 LYS HE 79 THR VAL 81 THRLEU 82 PHE ASN 76HISSER 78 LYS LE 79 THR VAL 81 TORLEU 82 HIS SN 76HISSER 78 LYS HE 79 THR VAL 81 THRLEU 82 TYR SN 76 HIS SER 78 LYS HE 79 VAL VAL 81 THR LEU 82 PHE ASN 76 H1S SER 78 LYS HE 79 VAL VAL 81 THR LEU 82 HIS SN 76 HIS SER 78 LYS ÍLE 79 VAL VAL 81 THR LEU 82 TYR SN 76 HIS SER 78 TYR HE 79 LEU VAL 81 TOR LEU 82 PHE ASN 76 H? S SER 78 TYR LE 79 LEU VAL 81 TOR LEU 82 HIS SN 76HISSER 78 TYR ÍLE 79 LEU VAL 81 THRLEU 82 TYR SN 76 H? S BE 78 TYR HE 79 MET VAL 81TORLEU 82 PHE ASN 76HISSER 78 TYR HE 79 MET VAL 81 THRLEU 82 HIS SN 76HISSER 78TYRHE 79 MET VAL 81 TORLEU 82 TYR SN 76HISSER 78 TYR HE 79THRVAL 81 TORLEU 82 PHE
ASN 76HISSER 78 TYR HE 79 TOR VAL 81 THR LEU 82 HIS SN 76 HJS SER 78 TYR HE 79THRVAL 81 THRLEU 82 TYR SN 76 HS SER 78 TYR ILE 79 VAL VAL 81 THR LEU 82 PHE ASN 76 H? S SER 78 TYR ILE 79 VAL VAL 81 TOR LEU 82 H? S SN 76 HIS SER 78 TYR LE 79 VAL VAL 81 TOR LEU 82 TYR LEU 75 LE BE 78 ASN HE 79 LEU VAL 81 TORLEU 82 PHE LEU 75 HE BE-ASN ¡¡ LE 79 LEU VAL 8 THRLEU 82H1S LEU 75 HE BE "8 ASN HE" 9 LEU VAL 81 THRLEU 8 TYR LEU 75 LE 78 BE ASN HE 79.MET VAL 81TO LEU 82 PHE LEU 75 ÍLE SER 78 ASN ÍLE 79 MET VAL 81 THRLEU 82HIS LEU 75 LE 78 BE ASN LE 79 MET VAL 81 TORLEU 82TYR LEU 75 HE BE 78 ASN LE 79 TOR VAL 81 THRLEU 82 PHE LEU 75 HE BE 78 ASN LE 79 THR VAL 81 THRLEU 8 HIS LEU 75 HE BE 78 ASN INLE 79 TOR VAL 81 TH LEU 82 TYR LEU 75 HE BE 78 ASN? LE 79 VAL VAL 81 THRLEU 82 PHE LEU 75 HE BE 7? ASN HE 79 VAL VAL 8 i THR LEU 82HIS LEU 75 WILL BE 78 ASN HE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 WILL BE 78 THR ÍLE 79 LEU VAL 8ITHRLEU 82 PHE LEU 75 WILL BE 78 THR HE 79 LEU VAL 81 TORLEU 82 HiS LEU 75 WILL BE 78 THR ÍLE 79 LEU VAL 81 THRLEU 82TYR 75 ILE BE 78 THR ÍLE 79 MET VAL 81 THRLEU 82 PHE LEU 75 ILE BE 78 THR HE 79 MET VAL 81 TORLEU 82HIS LEU 75 78 THR LE 79 MET VAL 81 TOR LEU 82 TYR LEU 75 HE BE 78 THR HE 79 TOR VAL 81 TORLEU 82 PHE LEU 75 ILE SER 7 $ THR LE 79 TOR VAL 81 TORLEU 82H1S
LEU 75 WILL BE 78 THR LE 79 THR VAL $ 1 TORLEU 82 TYR LEU 75 WILL BE 78 THR HE 79 VAL VAL 81 TOR LEU 82 PHE LEU 75 ILE SER 71 THR LE 79 VAL VAL 81 THR LEU 82 HiS LEU 75 HE BE 78 THR HE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 HE BE 7 $ ARGILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 HE BE 7 $ ARG LE 79 LEU VAL i THRLEU 82 H? S LEU 75 HE BE 7 »ARG? LE 79 LEU VAL $ 1 TORLEU 82 TYR LEU 75 HE BE 78 ARG ILE 79 MET VAL 81 TO LEU 82 PHH LEU 75 LE BE 78 ARG LE 79 MET VAL 81 TOR LEU 82HIS LEU 75 78 ARG LE 79 MET VAL 81TORLEU 82 TYR LEU 75 HE BE 78 ARG HE 79 THR VAL 81 TOR LEU 82 PHE LEU 75 HE BE 78 ARG HE 79 TOR VAL 8 TOR LEU id2 HIS
LEU 75? LE SER 7S ARG 1LE 79 TOR VAL If TOR LEU 82 TYR LEU 75 HE SER 71 ARG HE 79 VAL VAL 81 TO LEU 82 PHE LEU 75 HE BE 78 ARG HE 79 VAL VAL Yes TOR LEU 82 H? S LEU 75 I WILL BE 7S ARG LE 79 VAL VAL 8! TOR LEU 82TYR LEU 75? LE SER 78 ASP HE 79 LEU VAL 81 TOR LEU 82 PHE LEU 75 LE BE 7 $ ASP? LE 79 LEU VAL 1 TOR LEU 82 HIS LEU 7 1LE BE 7 $ ASP ILE 79 LEU VAL 81 THR LEU 82 TYR LEU 75? LE SER 78 ASP LE 79 MET VAL 81 H LEU 82 PHE LEU 75 HE BE 78 ASP LE 79 MET VAL 81 THRLEU 82 H? S LEU 75 HE BE 78 ASP HE 79 MET VAL 81 TH LEU 82 TYR LEU 75 ¡LE BE 78 ASP LE 79 THR VAL 81 THRLEU 82 PHE LEU 75 ÍLE SER 78 ASP HE 79 TOR VAL 81 THRLEU 82HIS LEU 75 HE BE 78 ASP ILE 79 THR VAL 81 TORLEU 82 TYR
LEU 75 HE BE 78 ASP HE 79 VAL VAL «i T? HR, * £ U 82 PHE LEU 75 HE BE 78 ASP HE 79 VAL VAL 8! THR LEU 82HIS LEU 75 HE BE 7SASPHE 79 VAL VAL 81 TO LEU 82 TYR LEU 75? LE SER 78 GLN HE 79 LEU VAL 81 THRLEU 82 PHE LEU 75 ILE SER 78 GLN LE 79 LEU VAL 81 THRLEU 82 HiS LEU 75 ÍLE SER 78 GLN ÍLE 79 LEU VAL 1 THR LEU 82 TYR LEU 75 ¡LE SER 78 GLN LE 79 MET VAL 81 THRLEU 82 PHE LEU 75 LE SER 78 GLN LE 79 MET VAL 81 TORLEU 82HIS LEU 75 ÍLE SER 78 GLN HE 79 MET VAL St TORLEU 82 TYR LEU 75 HE BE 78 GLN LE 79 THR VAL II TORLEU 82 PHE LEU 75 HE BE 78 GLN LE 79 THR VAL 81 TORLEU 82 HIS LEU 75 HE BE 78 GLN HE 79 TOR VAL $ l TORLEU 82TYR LEU 75 WILL BE 78 GLN HE 79 VAL VAL 81 TOR LEU 82 PHE LEU 75 WILL BE 78 GLN HE 79 VAL VAL 81 TOR LEU 82 HIS LEU 75? LE SER 78 GLN LE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 WILL BE 78 HIS HE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 ILE BE 78 H? S ILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 WILL BE 78 HIS? LE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 ILE BE 78 HIS ILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 WILL BE 78 H1S? LE 79 MET VAL 81 TOR LEU 82 HIS LEU 75 HE BE 78 HIS ILE 79 MET VAL 81 TOR LEU 82 TYR LEU 75 ILE BE 78 HIS HE 79 THR VAL 8 811 TOTORR LLEEUU 82 PHE LEU 75 HE BE 78 HIS LE 79 THR VAL 8811 TTHHRR LLEEUU 82 HIS LEU 75 ILE BE 78 HIS ILE 79 THR VAL 81 THR LEU 82 TYR LEU 75? LE SER 78 HIS ILE 79 VAL VAL 8 i TOR LEU 82 PHE LEU 75 I WILL BE 78 HIS ILE 79 VAL VAL 81 THR LEU 82 H1S LEU 75 HE BE 78 HIS LE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 WILL BE 78 LYS LE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 ILE BE 78 LYS HE 79 LEU VAL 81 THR LEU 82 HIS
LEU 75 WILL BE 78 LYS LE 79 LEU VAL 8¡ TOR LEU 82 TYR
LEU 75 WILL BE 78 LYS HE 79 MET VAL 81 TOR LEU 82 PHE
LEU 75 ILE BE 78 LYS ILE 79 MET VAL 8¡ TOR LEU 82 HIS
LEU 75 WILL BE 78 LYS ILE 79 MET VAL 81 THR LEU 82 TYR
LEU 75 HE BE 78 LYS ILE 79 THR VAL 81 THR LEU 82 PHE
LEU 75 HE BE 78 LYS ILE 79 THR VAL 81 TOR LEU 82 H? S
LEU 75 HE BE 78 LYS ILE 79 THR VAL 81 TOR LEU 82 TYR
LEU 75 ÍLE SER 78 LYS HE 79 VAL VAL 81 TOR LEU 82 PHE
LEU 75 HE BE 78 LYS HE 79 VAL VAL 81 TOR LEU 82 H? S
LEU 75 ÍLE SER 78 LYS LE 79 VAL VAL 81 THR LEU 82 TYR
LEU 75 ILE BE 78 TYR HE 79 LEU VAL 81 TOR LEU 82 PHE
LEU 75 HE BE 78 TYR ILE 79 LEU VAL 81 TOR LEU 82 HIS
LEU 75 HE BE 78 TYR LE 79 LEU VAL 81 TOR LEU 82 TYR
LEU 75 WILL BE 78 TYR LE 79 MET VAL 81 TOR LEU 82 PHE
LEU 75 HE BE 78 TYR HE 79 MET VAL 81 TOR LEU 82 HIS
LEU 75? LE SER 78 TYR HE 79 MET VAL 81 TOR LEU 82 T? R
LEU 75 HE BE 78 TYR HE 79 THR VAL 81 THR LEU 82 PHE
LEU 75 HE BE 78 TYR HE 79 THR VAL 81 TOR LEU 82 HIS
LEU 75 HE BE 78 TYR HE 79 THR VAL 81 TOR LEU 82 TYR
LEU 75 HE BE 78 TYR LE 79 VAL VAL 81 THR LEU 82 PHE
LEU 75 HE BE 78 TYR LE 79 VAL VAL 81 TOR LEU 82 HIS
LEU 75? LE BE 78 T? R HE 79 VAL VAL 81 TOR LEU 82 TYR
LEU 75 MET BE 78 ASN HE 79 LEU VAL 81 TOR LEU 82 PHE
LEU 75 MET BE 78 ASN HE 79 LEU VAL 81 THR LEU 82 HIS
LEU 75 MET BE 78 ASN ILE 79 LEU VAL 81 THR LEU 82 TYR
LEU 75 MET BE 78 ASN HE 79 MET VAL 81 THR LEU 82 PHE
LEU 75 MET BE 78 ASN HE 79 MET VAL 81 THR LEU 82 H? S
LEU 75 MET BE 78 ASN HE 79 MET VAL 81 TOR LEU 82 TYR
LEU 75 MET BE 78 ASN HE 79 THR VAL 8 THR LEU 82 PHE
LEU 75 MET BE 78 ASN ILE 79 THR VAL 81 THR LEU 82 HIS
LEU 75 MET BE 78 ASN HE 79 THR VAL 81 THR LEU 82 TYR
LEU 75 MET BE 78 ASN HE 79 VAL VAL 81 THR LEU 82 PHE
LEU 75 MET BE 78 ASN ILE 79 VAL VAL 81 TOR LEU 82 HIS
LEU 75 MET SER 78 ASN ILE 79 VAL VAL 81 THR LEU 82 TYR
LEU 75 MET BE 78 THR ILE 79 LEU VAL 81 TOR LEU 82 PHE
LEU 75 MET BE 78 TOR HE 79 LEU VAL 81 TOR LEU 82 HIS
LEU 75 MET BE 78 THR ILE 79 LEU VAL 81 TOR LEU 82 TYR
LEU 75 MET BE 78 TOR ILE 79 MET VAL 81 THR LEU 82 PHE
LEU 75 MET BE 78 TOR ILE 79 MET VAL 81 THR LEU 82 H1S LEU 75 MET SER 7g TOR LE 79 MET VAL 8! TOR LEU 82 TYR
LEU 75 MET BE 78 TOR HE 79 THR VAL 81 TOR LEU 82 PHE
LEU 75 MET BE 78 THR HE 79 TOR VAL 81 THR LEU 82 HIS
LEU 75 MET BE 78 THR LE 79 THR VAL 81 THR LEU 82 T? R
LEU 75 MET BE 78 TOR HE 79 VAL VAL 81 THR LEU 82 PHE
LEU 75 MET BE 78 THR HE 79 VAL VAL 8 i THR LEU 82 HIS
LEU 75 MET BE 78 TOR HE 79 VAL VAL 81 TOR LEU 82 TYR
LEU 75 MET BE 78 ARG HE 79 LEU VAL 81 TOR LEU 82 PHE
LEU 75 MET BE 78 ARG HE 79 LEU VAL 81 TO LEU 82 HIS
LEU 75 MET BE 78 ARG HE 79 LEU VAL 81 TH LEU 82 TYR
LEU 75 MET BE 78 ARG HE 79.MET VAL 81 TOR LEU 82 PHE
LEU 75 MET BE 78 ARG LE 79 MET VAL 8! TOR LEU 82 HIS
LEU 75 MET BE 78 ARG LE 79 MET VAL 81 THR LEU 82 TYR
LEU 75 MET BE 78 ARG HE 79 THR VAL 81 THR EU 82 PHE
LEU 75 MET BE 78 ARG ÍLE 79 TOR VAL 81 THR LEU 82 HJS
LEU 75 MET BE 78 ARG LE 79 THR VAL 81 THR LEU 82 T? R
LEU 75 MET BE 78 ARG LE 79 VAL VAL 81 THR LEU 82 PHE
LEU 75 MET BE 78 ARG HE 79 VAL VAL 81 TOR LEU 82 HIS
LEU 75 MET BE 78 ARG ÍLE 79 VAL VAL 1 TOR LEU 82 TYR
LEU 75 MÉT SER 78 ASP ÍLE 79 LEU VAL 1 TOR LEU 82 PHE
LEU 75 MET BE 78 ASP LE 79 LEU VAL 1 TOR LEU 82 HIS
LEU 75 MET BE 78 ASP HE 79 LEU VAL 81 THR LEU 82 T? R
LEU 75 MET BE 78 ASP LE 79 MET VAL 81 THR LEU 82 PHE
LEU 75 MET BE 78 ASP HE 7 ET VAL SI THR LEU 82 HIS
LEU 75 MET BE 78 ASP HE 79 MET VAL 81 TOR LEU 82 TYR
LEU 75 MET BE 78 ASP HE 79 THR VAL Yes TOR LEU 82 PHE
LEU 75 MET BE 78 ASP HE 79 THR VAL 81 TH LEU 82 H¡S
LEU 75 MET BE 78 ASP LE 79 THR VAL 81 THR LEU 82 TYR
LEU 75 MET BE 78 ASP ILE 79 VAL VAL 81 TOR LEU 82 PHE
LEU 75 MET BE 78 ASP LE 79 VAL VAL 81 TOR LEU 82 HIS
LEU 75 MET BE 78 ASP HE 79 VAL VAL 81 TOR LEU 82 TYR
LEU 75 MET BE 78 GLN ILE 79 LEU VAL 81 TOR LEU 82 PHE
LEU 75 MET SER 71 GLN HE 79 LEU VAL 8¡ TOR LEU 82 HIS
LEU 75 MET BE 78 GLN LE 79 LEU VAL 81 TOR LEU 82 TYR
LEU 75 MET BE 78 GLN LE 79 MET VAL 81 TOR LEU 82 PHE
LEU 75 MET BE 78 GLN LE 79 MET VAL 81 THR LEU 82 H¡S
LEU 75 MET BE 78 GLN HE 79 MET VAL 81 TH LEU 82 T? R
LEU 75 MET BE 78 GLN HE 79 THR VAL 81 TOR LEU 82 PHE
LEU 75 MET SER 78 GLN HE 79 THR VAL 81 TOR LEU 82 HIS
LEU 75 MET SER 78 GLN HE 79 THR VAL 81 TOR LEU 82 TYR
LEU 75 MET BE 78 GLN HE 79 VAL VAL 81 TOR LEU 82 PHE
LEU 75 .MET SER 78 GLN HE 79 VAL VAL 81 TOR LEU 82 HIS
LEU 75 MET SER 78 GLN ILE 79 VAL VAL 81 TOR LEU 82 TYR
LEU 75 MET BE 78 HIS ILE 79 LEU VAL 81 TOR LEU 82 PHE
LEU 75 MET BE 78 HIS HE 79 LEU VAL 81 TUR LEU 82 HIS
LEU 75 MET BE 78 H1S LE 79 LEU VAL 81 TOR LEU 82 TYR
LEU 75 MET BE 78 HiS HE 79 MET VAL 81 THR LEU 82 PHE
LEU 75 MET BE 78 H? S ÍLE 79 MET VAL 81 THR LEU 82 H? S
LEU 75 MET BE 78 HIS HE 79 MET VAL 81 TOR LEU 82 TYR
LEU 75 MET BE 78 H? S ÍLE 79 THR VAL 81 THR LEU 82 PHE
LEU 75 MET BE 78 H? S HE 79 TOR VAL 81 TOR LEU 82 HIS
LEU 75 MET BE 78 HIS ILE 79 THR VAL 81 THR LEU 82 TYR
LEU 75 MET BE 78 HIS HE 79 VAL VAL 81 THR LEU 82 PHE
LEU 75 MET BE 78 HIS ÍLE 79 VAL VAL 8 i THR LEU 82 HIS
LEU 75 MET BE 78 HIS ILE 79 VAL VAL 81 TOR LEU 82 TYR
LEU 75 MET BE 78 LYS ILE 79 LEU VAL 81 THR LEU 82 PHE LEU "5 MET BE 78 LYS LE 79 LEU VAL 81 THR LEU- 82 H? S LEU 75 MET BE 78 LYS LE 79 LEU VAL Y TORLEU 82 TYR LEU 75 MET BE 78 LYS HE 79 MET VAL 81 THR LEU 82 PHE LEU 75 MET BE 78 LYS ÍLE 79 MET VAL 8! THRLEU 82 HiS LEU 75 i ET SER 78 LYS ILE 79 MET VAL 81 THRLEU 82TYR LEU 75 MET SER 78 LYS HE 79 TOR VAL 8! THRLEU 82 PHE LEU 75 MET SER 78 LYS ÍLE "» 9 TOR VAL Yes TOR LEU 82HIS LEU 75 MET SER 78 LYS ÍLE 79 THR VAL 81 THRLEU 82 TYR LEU 75 MET SER 78 LYS ÍLE 79 VAL VAL 81 TORLEU 82 PHE LEU 75 MET BE 78 LYS LE 79 VAL VAL 81 THR LEU 82HIS LEU 75 MET BE 78 LYS LE 79 VAL VAL 81 THRLEU 82TYR LEU 75 MET BE 78 TYR HE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 MET BE 78 TYR LE 79 LEU VAL 81 THR LEU 82H1S LEU 75 MET BE 78 TYR HE 79 LEU VAL 81 TOR LEU 8 TYR LEU 75 MET BE 78 TYR HE 79 MET VAL 81 TH LEU 82 PHE LEU 75 MET SER 78TYRHE 79 MET VAL 81 THR LEU 82HIS LEU 75 MET BE 78 TYR LE 79 MET VAL 81 THR LEU 82TYR LEU 75 MET SER 78 TYR I LE 79 TOR VAL 81 TO LEU 82 PHE LEU 75 MET SER 78 TYR LE 79 TOR VAL 81 THRLEU 82HIS LEU 75 MET SER 78 TYR LE 79 THR VAL 81 THR LEU 82TYR LEU 75 MET SER 78 TYR HE 79 VAL VAL 81 TOR LEU 82 PHE LEU 75 MET BE 78 TYR HE 79 VAL VAL 81 THR LEU 82HIS LEU 75 MET SER 78TYRILE 79 VAL VAL 81 TORLEU 82 TYR LEU 75 VAL SER 78 ASN HE 79 LEU VAL 81 TO LEU 82 PHE LEU 75 VAL SER 78 ASN HE 79 LEU VAL 81 TORLEU 82HIS LEU 75 VAL SER 78 ASN? LE 79 LEU VAL 81TH LEU 82TYR LEU 75 VAL SER 78 ASN HE 79 MET VAL 81 THRLEU 82 PHE LEU 75 VAL SER 78 ASN HE 79 MET VAL 81 TORLEU S2HIS LEU 75 VAL SER 78 ASN HE 79 MET VAL 8ITORLEU 82TYR LEU 75 VAL SER 78 ASN? LE 79 THR VAL 81 TORLEU 82 PHE LEU 75 VAL SER 78 ASN ILE 79 THR VAL 81 TOR LEU 82HIS LEU 75 VAL SER 78 ASN HE 79 THR VAL 81 THRLEU 82 TYR LEU 75 VAL SER 78 ASN HE 79 VAL VAL 81THRLEU 82 PHE LEU 75 VAL SER 78 ASN ÍLE 79 VAL VAL 81 THR LEU 82H1S LEU 75 VAL SER 78 ASN ILE 79 VAL VAL 81TORLEU 82 TYR LEU 75 VAL SER 78 TOR LE 79 LEU VAL 81 THRLEU 82 PHE LEU 7 5 VAL SER 78 TOR HE 79 LEU VAL 81 THRLEU 82 H? S LEU 75 VAL SER 78 THR HE 79 LEU VAL 81 TORLEU 82 TYR LEU 75 VAL SER 78 TOR HE 79 MET VAL 81 TOR LEU 82 PHE LEU 75 VAL SER 78 TOR HE 79 MET VAL 81 THR LEU 82HIS LEU 75 VAL SER 78 TOR HE 79 MET VAL 81 THR LEU 82 TYR LEU 75 VAL SER 78 TOR HE 79THRVAL 8I HRLEU 82 PHE LEU 75 VAL SER 78THRHE 79 THR VAL 81 TOR LEU 82HIS LEU 75 VAL SER 78 TOR ILE 79 THR VAL 81 TOR LEU 82 TYR LEU 75 VAL SER 78 THR HE 79 VAL VAL 81 THRLEU 82 PHE LEU 75 VAL SER 78 TOR ILE 79 VAL VAL 81 THRLEU 82HIS LEU 75 VAL SER 78 TOR HE 79 VAL VAL 81 THR LEU 82TYR LEU 75 VAL SER 78 ARG HE 79 LEU VAL 81 TOR LEU 82 PHE LEU 75 VAL SER 78 ARG? LE 79 LEU VAL 81 TORLEU 82 H? S LEU 75 VAL SER 78 ARG LE 79 LEU VAL 81 TOR LEU 82TYR LEU 75 VAL SER 78 ARG LE 79 MET VAL 81 TO LEU 82 PHE LEU 75 VAL SER 78 ARG LE 79 MET VAL 81 TORLEU 82HIS LEU 75 VAL SER 78 ARG LE 79 MET VAL 81 THR LEU 82 TYR LEU 75 VAL SER 78 ARG HE 79 THR VAL 81 TOR LEU 82 PHE LEU 75 VAL SER 78 ARG ÍLE 79 THR VAL 81 THR LEU 82 H? S LEU 75 VAL SER 78 ARG ILE 79 THR VAL 81 THRLEU 82TYR LEU 75 VAL SER 78 ARG HE 79 VAL VAL 81 TH LEU 82 PHE
LEU 75 VAL SER 78 ARG HE VAL VAL 81 THR LEU 82 H¡S
LEU 75 VAL SER 78 ARG LE 79 VAL VAL 81 TOR LEU 82 TYR
LEU 75 VAL SER 78 ASP LE 79 LEU VAL 81 THR LEU 82 PHE
LEU 75 VAL SER 78 ASP HE 79 LEU VAL 81 THR LEU 82 HIS
LEU 75 VAL SER 78 ASP ILE 79 LEU VAL 81 THR LEU 82 TYR
LEU 75 VAL SER 78 ASP HE 79 MET VAL 81 THR LEU 82 PHE
LEU 75 VAL SER 78 ASP HE 79 MET V AL 81 TOR LEU 82 HIS
LEU 75 VAL SER 78 ASP? LE 79 MET VAL 81 TOR LEU 82 TYR
LEU 75 VAL SER 78 ASP HE 79 THR VAL 81 THR LEU 82 PHE
LEU 75 VAL SER 78 ASP LE 79 TOR VAL 81 TOR LEU 82 H¡S
LEU 75 VAL SER 78 ASP LE 79 TOR VAL 81 THR LEU 82 TYR
LEU 75 VAL SER 78 ASP LE 79 VAL VAL 81 THR LEU 82 PHE
LEU 75 VAL SER 78 ASP LE 79 '- AL VAL 81 THR LEU 82 HIS
LEU 75 VAL SER 78 ASP HE 79 VAL VAL 81 THR LEU 82 TYR
LEU 75 VAL SER 78 GLN ILE 9 LEU VAL 81 THR LEU 82 PHE
LEU 75 VAL SER 78 GLN LE 79 LEU VAL 8! TOR LEU 82 H? S
LEU 75 VAL SER 78 GLN ÍLE 79 LEU VAL 81 TOR LEU 82 TYR
LEU 75 VAL SER 78 GLN HE 79 MET VAL 81 THR LEU 82 PHE
LEU 75 VAL SER 78 GLN HE 79 MET VAL 81 TOR LEU 82 H1S
LEU 75 VAL SER 78 GLN HE 79 MET VAL 81 TOR LEU 82 TYR
LEU 75 VAL SER 78 GLN HE 79 TOR VAL 81 THR LEU 82 PHE
LEU 75 VAL SER 78 GLN HE 79 TOR VAL 81 TOR LEU 82 H? S
LEU 75 VAL SER 78 GLN HE 79 TOR VAL 81 THR LEU 82 TYR
LEU 75 VAL SER 78 GLN LE 79 VAL VAL 81 TOR LEU 82 PHE
LEU 75 VAL SER 78 GLN ÍLE 79 VAL VAL 81 TOR LEU 82 H? S
LEU 75 VAL SER 78 GLN HE 79 VAL VAL 81 TOR LEU 82 T? R
LEU 75 VAL SER 78 HIS LE 79 LEU VAL 81 THR LEU 82 PHE
LEU 75 VAL SER 78 HIS ILE 79 LEU VAL 81 THR LEU 82 HIS
LEU 75 VAL SER 78 HIS ILE 79 LEU VAL 81 TOR LEU 82 TYR
LEU 75 VAL SER 78 HIS ILE 79 MET VAL 81 TOR LEU 82 PHE
LEU 75 VAL SER 78 HIS HE 79 MET VAL 81 THR LEU 82 HIS
LEU 75 VAL SER 7 HIS HE 79 MET VAL 81 TOR LEU 82 TYR
LEU 75 VAL SER 78 HIS HE 79 TOR VAL 81 THR LEU 82 PHE
LEU 75 VAL SER 78 HIS HE 79 TOR VAL 81 THR LEU 82 H1S
LEU 75 VAL SER 78 H? S? LE 79 THR VAL 81 THR LEU 82 TYR
LEU 75 VAL SER 78 HIS ILE 79 VAL VAL 81 THR LEU 82 PHE
LEU 75 VAL SER 78 HIS HE 79 VAL VAL 81 THR LEU 82 HIS
LEU 75 VAL SER 78 HIS ÍLE 79 VAL VAL 81 TOR LEU 82 TYR
LEU 75 VAL SER 78 LYS? LE 79 LEU VAL 81 TOR LEU 82 PHE
LEU 75 VAL SER 78 LYS ILE 79 LEU VAL 81 TOR LEU 82 H? S
LEU 75 VAL SER 78 LYS HE 79 LEU VAL 81 THR LEU 82 TYR
LEU 75 VAL SER 78 LYS HE 79 MET VAL 81 THR LEU 82 PHE
LEU 75 VAL SER 78 LYS HE 79 MET VAL 81 THR LEU 82 HIS
LEU 75 VAL SER 78 LYS LE 79 MET VAL 81 TOR LEU 82 T? R
LEU 75 VAL SER 78 LYS LE 79 THR VAL 81 THR LEU 82 PHE
LEU 75 VAL SER 78 LYS? LE 7 THR VAL Yes TOR LEU 82 HIS
LEU 75 VAL SER 78 LYS ÍLE 79 THR VAL 81 THR LEU 82 TYR
LEU 75 VAL SER 78 LYS LE 79 VAL VAL 8? THR LEU 82 PHE
LEU 75 VAL SER 78 LYS? LE 79 VAL VAL 81 THR LEU 82 H1S
LEU 75 VAL SER 78 LYS ILE 79 VAL VAL 81 THR LEU 82 TYR
LEU 75 VAL SER 78 TYR ÍLE 79 LEU VAL 81 THR LEU 82 PHE
LEU 75 VAL SER 78 TYR ILE 79 LEU VAL 81 TOR LEU 82 HIS
LEU 75 VAL SER 78 TYR HE 79 LEU VAL 81 TOR LEU 82 T? R
LEU 75 VAL SER 78 TYR HE 7 MET VAL 81 TOR LEU 82 PHE
LEU 75 VAL SER 78 TYR HE 79 ET VAL 81 TOR LEU 82 H1S LEU 75 VAL SER 78 TYR HE 79 MET VAL 81 TOR LEU 82 T? R LEU 75 VAL SER 78 TYR HE 79 THR VAL 8! THR LEU 82 PHE LEU 75 VAL SER 78 TYR HE 79 TOR VAL 81 THR LEU 82 HIS LEU 75 VAL SER 78 T? R HE 79 TOR VAL 81 TOR LEU 82 TYR LEU 75 VAL SER 78 TYR ÍLE 79 VAL VAL 81 TOR LEU 82 PHE LEU 75 VAL SER 78 TYR HE 79 VAL VAL 81 TOR LEU 82 H1S LEU 75 VAL SER 78 TYR HE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 HE ASN 76 HIS HE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 HE ASN 76 HIS ILE 79 LEU VAL 81 TOR LEU 82 HIS LEU 75 LE ASN 76 H1S HE 79 LEU VAL 81 TOR LEU 82 TYR LEU 75 HE ASN 76 HIS HE 7 ET VAL 81 TOR LEU 82 PHE LEU 75 HE ASN 76 HIS LE 79 MET VAL 81 TOR LEU 82 HIS LEU 75 HE ASN 76 HIS ILE 79 MET VAL 81 TOR LEU 82 TYR LEU 75 HE ASN 76 HIS HE 79 TOR VAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS HE 79 TOR VAL 81 THR LEU 82 H? S LEU 75 HE ASN 76 HIS ILE 79 TOR VAL 81 THR LEU 82 TYR LEU 75 ILE ASN 76 HIS ILE 79 VAL VAL 81 THR LEU 82 PHE LEU 75 H ASN 76 HIS HE 79 VAL VAL 8! THR LEU 82 HIS LEU 75 ILE ASN 76 HISEL 79 VAL VAL 81 THR LEU 82 TYR
LEU 75 MET ASN 76 HIS LE 79 LEU VAL 1 TOR LEU 82 PHE LEU 75 MET ASN 76 HIS HE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HIS LE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 MET ASN 76 HIS HE 79 MET VAL 81 TOR LEU 82 PHE LEU 75 MET ASN 76 HIS ILE 79 MET VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HIS ILE 79 MET VAL 81 THR LEU 82 TYR LEU 75 MET ASN 76 HIS ILE 79 TOR VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HIS HE 79 THR VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HIS HE 79 TOR VAL 81 THR LEU 82 T? R LEU 75 MET ASN 7 HIS HE 79 VAL VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HIS ILE 79 VAL VAL 81 TOR LEU 82 HIS LEU 75 MET ASN 76 HIS HE 79 VAL VAL 81 TOR LEU 82 TYR LEU 75 VAL ASN 76 HIS LE 79 LEU VAL 81 TOR LEU 82 PHE
LEU 75 VAL ASN 76 HIS LE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 VAL ASN 76 HIS ILE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS HE 79 MET VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 HISELE 79 MET VAL 81 TOR LEU 82 HIS LEU 75 VAL ASN 76 HIS LE 79 MET VAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS ILE 79 TOR VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 HIS HE 79 THR VAL 8¡ THR LEU 82 H? S LEU 75 VAL ASN 76 HIS HE 79 TOR VAL 1 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS HE 79 VAL VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 HIS HE 79 VAL VAL 81 TOR LEU 82 HIS LEU 75 VAL ASN 76 HiS HE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 HE ASN 76 HIS SER 78 ASN VAL 81 THR LEU 82 PHE
LEU 75? LE ASN 76 H? S SER 78 ASN VAL 81 TOR LEU 82 HIS LEU 75 LE ASN 76 HIS BE 78 ASN VAL 81 THR LEU 82 T? R LEU 75 H ASN 76 HIS BE 78 TOR VAL 81 THR LEU 82 PHE LEU 75 HE ASN 76 HIS BE 78 TOR VAL 81 THR LEU 82 HIS LEU 75 HE ASN 76 HIS BE 78 TOR VAL 8¡ TOR Lpj 82 TYR LEU 75 ILE ASN 76 H? S SER 78 ARG VAL 81 THR L _U 82 PHE LEU 75 ILE ASN 76 HIS BE 78 ARG VAL 81 TOR LEU 82 HIS LEU 75 LE ASN 76 H1S SER 78 GLN VAL 81 THR LEU 82 HIS LEU 75 HE ASN 76 HIS SER 78 GLN VAL 81 TOR LEU 82 TYR LEU 75 HE ASN 76 HIS BE 78 HIS VAL 8! THR LEU 82 PHE LEU 75 LE ASN 76 HIS BE 78 H¡S VAL 81 TOR LEU 82 HIS LEU 75 HE ASN 76 HiS SER 78 HIS VAL 81 TOR LEU 82 TYR LEU 75 HE ASN 76 HIS BE 78 LYS VAL 81 THR LEU 82 PHE LEU 75 HE ASN 76 HIS BE 78 LYS VAL 81 TOR LEU 82 HIS LEU 75 HE ASN 76 H1S BE 78 LYS VAL 81 TOR LEU 82 T? R LEU 75 HE ASN 76 HIS BE 78 TYR VAL 81 TOR LEU 82 PHE LEU 75 HE ASN 76 HIS BE 78 TYR VAL 81 TOR LEU 82 HiS LEU 75 HE ASN 76 HH S SER 78 TYR VAL 81 THR LEU S2 TYR LEU 75 MET ASN 76 HIS SER 78 ASN VAL 81 TOR LEU 82 PHE LEU 75 MET ASN 76 HiS SER 78 ASN VAL 81 THR LEU 82 H1S LEU 75 MET ASN 76 HIS SER 78 ASN VAL 81 TOR LEU 82 TYR LEU 75 MET ASN 76 H1S SER 78 THR VAL 81 TOR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 THR VAL 81 THR LEU 82 HtS LEU 75 MET ASN 76 HIS BE 78 TOR VAL 81 TOR LEU 82 T? R LEU 75 MET ASN 76 HIS SER 78 ARG VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 ARG VAL 81 THR LEU 82 H1S
LEU 75 MET ASN 76 HIS SER 78 ARG VAL 81 THR LEU 82 TYR LEU 75 MET ASN 76 HiS SER 78 ASP VAL 81 TOR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 ASP VAL 81 TOR LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 ASP VAL 81 TOR LEU 82 T? R LEU 75 MET ASN 76 H1S SER 78 GLN VAL 81 TH LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 GLN VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 H? S SER 78 GLN VAL 81 THR LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 HIS VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 HIS VAL 81 TOR LEU 82 HIS LEU 75 MET ASN 76 H1S SER 78 HIS VAL 81 THR LEU 82 T? R LEU 75 MET ASN 7 HIS SER 78 LYS VAL 81 TOR LEU 82 PHE LEU 75 MET ASN 76 H1S SER 78 LYS VAL 81 THR LEU 82 HIS
LEU 75 MET ASN 76 HIS SER 78 LYS VAL 81 TOR LEU 82 TYR LEU 75 MET ASN 76 HJS SER 78 TYR VAL 81 TH LEU 82 PHE LEU 75 MET ASN 76 HiS SER 78 TYR VAL 81 TOR LEU 82 HiS LEU 75 MET ASN 76 HIS SER 78 TYR VAL 81 TOR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 ASN VAL 81 TOR LEU 82 PHE LEU 75 VAL ASN 76 H? S SER 78 ASN VAL 81 TOR LEU 82 HIS LEU 75 VAL ASN 76 HiS SER 78 ASN VAL 81 TOR LEU 82 TYR LEU 75 VAL ASN 76 H? S SER 78 THR VAL 8! TOR LEU 82 PH LEU 75 VAL ASN 76 HIS SER 78 TOR VAL 81 TOR LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 TOR VAL 81 TOR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 ARG VAL 1 THR LEU 82 PHE LEU 75 VAL ASN 76 H? S SER 78 ARG VAL 81 TOR LEU 82 HiS LEU 75 VAL ASN 76 H? S SER 78 ARG VAL 81 TOR LEU 82 TYR
LEU 75 VAL ASN 76 HIS SER 78 ASP VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 H? S SER 78 ASP VAL 81 THR LEU 82 HiS LEU 75 VAL ASN 76 HIS SER 78 ASP VAL 81 THR LEU 82 T? R LEU 75 VAL ASN 76 H1S SER 78 GLN VAL 81 TOR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 GLN VAL 81 TOR LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 GLN VAL 81 TOR LEU 82 TYR LEU 75 VAL ASN 76 HIS BE 78 H1S VAL 81 THRLEU 82 PHE LEU 75 VAL ASN 76 HIS BE 78 HIS VAL 81 THR LEU 82 HIS LEU 75 VAL ASN 76 HIS BE 78 HIS VAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS BE 78 LYS VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 H? S SER 78 LYS VAL 81 TOR LEU 82 H1S LEU 75 VAL ASN 76 HIS SER 78 LYS VAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76 HJS SER 78 TYR VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 HiS SER 78 TYR VAL 81 THR LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 TYR VAL 81 THR LEU 82 TYR LEU 75 HE ASN 76 H? S SER 78 ASN HE 79 LEU LEU 82 PHE LEU 75 HE ASN 76 HiS SER 78 ASN LE 79 LEU LEU 82 H1S LEU 75 HE ASN 76 HIS BE 78 ASN HE 79 LEU LEU 82 T YR LEU 75 ILE ASN 76 HIS BE 78 ASN HE 79 MET LEU 82 PHE LEU 75 HE ASN 76 HiS SER 78 ASN ILE 79 MET LEU 82 HIS LEU 75 HE ASN 76 HIS BE 78 ASN HE 79 MET LEU 82 TYR LEU 75 HE ASN 76 HIS BE 78 ASN LE 79 THR LEU 82 PHE LEU 75 HE ASN 76 H1S BE 78 ASN? LE 79 THR LEU 82 H? S LEU 75 HE ASN 76 H? S BE 78 ASN HE 79 THR LEU 82 TYR LEU 75? LE ASN 76 HIS BE 78 ASN HE 79 VAL LEU 82 PHE LEU 75 ILE ASN 76 HIS BE 78 ASN? LE 79 VAL LEU 82 HIS LEU 75 ILE ASN 76 H? S SER 78 ASN ILE 79 VAL LEU 82 TYR LEU 75 ? LE ASN 76 HIS BE 78 THR HE 79 LEU LEU 82 PHE LEU 75 HE ASN 76 H1S BE 78 THR HE 79 LEU LEU 82 HIS LEU 75 ILE ASN 76 HIS BE 78 THR HE 79 LEU LEU 82 TYR LEU 75 ILE ASN 76 HIS BE 78 THR HE 79 MET LEU 82 PHE LEU 75 HE ASN 76 HIS BE 78 THR INE 79 MET LEU 82 HIS LEU 75 HE ASN 76 H? S BE 78 THR HE 79 MET LEU 82 TYR LEU 75 ILE ASN 76 H1S BE 78 THR ÍLE 79 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS BE 78 THR ILE 79 THR LEU 82 HIS LEU 75 HE ASN 76 HIS BE 78 THR HE 79 THR LEU 82 TYR LEU 75 HE ASN 76 H1S BE 78 THR HE 79 VAL LEU 82 PHE LEU 75 ILE ASN 76 HIS BE 78 THR HE 79 VAL LEU 82 HIS LEU 75 HE ASN 76 HIS BE 78 THR HE 79 VAL LEU 82 TYR LEU 75 ILE ASN 76 H? S BE 78 ARG ÍLE 79 LEU LEU 82 PHE LEU 75 HE ASN 76 HIS BE 78 ARG HE 79 LEU LEU 82 H1S LEU 75 HE ASN 76 HIS BE 78 ARG ILE 79 LEU LEU 82 TYR LEU 75 HE ASN 76 HIS BE 78 ARG HE 79 MET LEU 82 PHE LEU 75 HE ASN 76 H1S SER 78 ARG? LE 79 MET LEU 82 HIS LEU 75 ILE ASN 76 H? S SER 78 ARG ILE 79 MET LEU 82 TYR LEU 75 HE ASN 76 HiS SER 78 ARG ILE 79 THR LEU 82 PHE LEU 75 HE ASN 76 HIS BE 78 ARG ILE 79 THR LEU 82 HIS LEU 75 HE ASN 76 HIS BE 78 ARG? LE 79 THR LEU 82 TYR LEU 75 ILE ASN 76 HIS BE 78 ARG 1LE 79 VAL LEU 82 PHE LEU 75 ILE ASN 76 HIS BE 78 ARG ILE 79 VAL LEU 82 HIS LEU 75 HE ASN 76 H? S BE 78 ARG ILE 79 VAL LEU 82 T? R LEU 75 ILE ASN 76 HIS BE 78 ASP HE 79 LEU LEU 82 PHE
LEU 75 ILE ASN 76 HIS BE 78 ASP? LE 79 LEU LEU 82 HIS LEU 75 HE ASN 76 HIS BE 78 ASP HE 79 LEU LEU 82 TYR LEU 75 HE ASN 76 HIS BE 78 ASP ILE 79 MET LEU 82 PHE LEU 75 HE ASN 76 HIS BE 78 ASP HE 79 MET LEU 82 HIS LEU 75 HE ASN 76 H? S BE 78 ASP HE 79 MET LEU 82 TYR LEU 75 ILE ASN 76 HIS BE 78 ASP HE 79 THR LEU 82 PHE
LEU 75? LE ASN 76 HiS SER 78 ASP ILE 79 THR LEU 82 H? S LEU 75 ILE ASN 76 HIS BE 78 ASP 1LE 79 THR LEU 82 TYR LEU 75 HE ASN 76 H1S SER 78 ASP HE 79 VAL LEU 82 PHE
LEU 75 HE ASN 76 HIS BE 78 ASP ILE 79 VAL LEU 82 HIS LEU 75 ILE ASN 76 HIS BE 78 ASP HE 79 VAL LEU 82 T? R LEU 75 ILE ASN 76 HIS SER 78 GLN ILE 79 LEU LEU 82 PHE
LEU 75 ILE ASN 76 HIS BE 78 GLN LE 79 LEU LEU 82 HIS LEU 75 LE ASN 76 HIS BE 78 GLN LE 79 LEU LEU 82 TYR LEU 75 HE ASN 76 H1S SER 78 GLN ILE 79 MET LEU 82 PHE
LEU 75 ILE ASN 76 HIS BE 78 GLN? LE 79 MET LEU 82 HIS LEU 75 HE ASN 76 HIS BE 78 GLN ILE '' 9 MET LEU 82 TYR LEU 75? LE ASN 76 HIS TO BE "8 GLN ÍLE 79 TOR LEU 82 PHE LEU 75 ÍLE ASN 76 HJS SER 78 GLN ÍLE 79 TOR LEU 82 H? S LEU 75 LE ASN 76 HIS BE 78 GLN ILE 79 TOR LEU 82 TYR LEU 75 LE ASN 76 HIS BE 78 GLN LE 79 VAL LEU 82 PHE LEU 75 LE ASN 76 HIS BE 78 GLN LE 79 VAL LEU 82 HIS LEU 75 HE ASN 76 HIS BE 78 GLN LE 79 VAL LEU 82 TYR LEU 75 HE ASN 76 HIS BE 78 HIS ILE 79 LEU LEU 82 PHE LEU 75 ILE ASN 76 HIS BE 78 HIS ILE 79 LEU LEU 82 HIS LEU 75 LE ASN 76 HIS BE 78 HIS ILE 79 LEU LEU 82 TYR LEU 75 HE ASN 76 HIS BE 78 H1S ILE 79 MET LEU 82 PHE LEU 75 LE ASN 76 HJS SER 78 HIS ILE 79 MET LEU 82 HiS LEU 75 HE ASN 76 H? S BE 78 HIS HE 79 MET LEU 82 TYR LEU 75 LE ASN 76 H? S BE 78 HIS HE 79 TOR LEU 82 PHE LEU 75 LE ASN 76 HIS BE 78 HiS ILE 79 TOR LEU 82 HIS LEU 75 HE ASN 76 HIS BE 78 HIS? LE 79 THR LEU 82 TYR LEU 75 ILE ASN 76 H1S BE 78 HIS ILE 79 VAL LEU 82 PHE LEU 75 LE ASN 76 HIS BE 78 HIS HE 79 VAL LEU 82 HIS LEU 75 HE ASN 76 HIS BE 78 HIS 1LE 79 VAL LEU 82 T? R LEU 75 LE ASN 76 H? S BE 78 LYS LE 79 LEU LEU 82 PHE LEU 75 HE ASN 76 H? S BE 78 LYS ILE 79 LEU LEU 82 HIS LEU 75 HE ASN 76 HIS BE 78 LYS? LE 79 LEU LEU 82 TYR
LEU 75 HE ASN 76 HIS BE 78 LYS HE 79 MET LEU 82 PHE LEU 75 ILE ASN 76 HIS BE 78 LYS ILE 79 MET LEU 82 HIS LEU 75 HE ASN 76 HIS BE 78 LYS ILE 79 MET LEU 82 TYR LEU 75 HE ASN 76 HIS BE 78 LYS ILE 79 TOR LEU 82 PHE LEU 75 HE ASN 76 HIS BE 78 LYS ILE 79 TOR LEU 82 HiS LEU 75 HE ASN 76 HIS BE 78 LYS HE 79 TOR LEU 82 TYR LEU 75 ILE ASN 76 HIS BE 78 LYS ILE 79 VAL LEU 82 PHE LEU 75 HE ASN 76 HIS BE 78 LYS HE 79 VAL LEU 82 HIS LEU 75 HE ASN 76 HIS BE 78 LYS HE 79 VAL LEU 82 TYR LEU 75 ILE ASN 76 HIS BE 78 TYR ILE 79 LEU LEU 82 PHE LEU 75 HE ASN 76 H? S BE 78 TYR HE 79 LEU LEU 82 HIS LEU 75 HE ASN 76 HIS BE 78 TYR HE 79 LEU LEU 82 T? R LEU 75 ILE ASN 76 HIS BE 78 TYR ILE 79 MET LEU 82 PHE
LEU 75 HE ASN 76 HIS BE 78 TYR HE 79 MET LEU 82 HIS LEU 75 HE ASN 76 HIS BE 78 T? R HE 79 MET LEU 82 TYR LEU 75 HE ASN 76 HIS BE 78 T? R HE 79 TOR LEU 82 PHE LEU 75 ILE ASN 76 H? S BE 78 TYR HE 79 TOR LEU 82 H1S LEU 75 LE ASN 76 H? S BE 78 TYR ILE 79 THR LEU 82 TYR LEU 75? LE ASN 76 H1S SER 78 TYR 1LE 79 VAL LEU 82 PHE LEU 75 HE ASN 76 H? S BE 78 TYR ILE 79 VAL LEU 82 HIS LEU 75 ILE ASN 76 H1S SER 78 TYR HE 79 VAL LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 ASN ILE 79 LEU LEU 82 PHE LEU 75 MET ASN 76 H1S SER 78 ASN HE 79 LEU LEU 82 HiS LEU 75 ET ASN 76 H? S BE 78 ASN HE 79 LEU LEU 82 TYR LEU 75 MET ASN 76 HIS BE 78 ASN HE 79 MET LEU 82 PHE
LEU 75 MET ASN 76 H1S SER 78 ASN 1LE 79 MET LEU 82 H? S LEU 75 MET ASN 7 HIS SER 78 ASN HE 79 MET LEU 82 T? R LEU 75 MET ASN 76 HIS BE 78 ASN HE 79 TOR LEU 82 PHE LEU 75 MET ASN 76 HIS BE 78 ASN ILE 79 THR LEU 82 H1S LEU 75 MET ASN 76 HIS BE 78 ASN HE 79 TOR LEU 82 TYR LEU 75 MET ASN 76 HIS BE 78 ASN ILE 79 VAL LEU 82 PHE LEU 75 MET ASN 76 H? S SER 78 ASN ILE 79 VAL LEU 82 HiS LEU 75.MET ASN 76 H1S SER 78 ASN ILE 79 VAL LEU 82 TYR LEU 75 MET ASN 76 HIS BE 78 TOR? LE 79 LEU LEU 82 PHE LEU 75 MET ASN 76 HiS BE 78 THR HE 79 LEU LEU 82 HIS
LEU 75 MET ASN 76 HIS BE 78 THR ÍLE 79 LEU LEU 82 TYR
LEU 75 MET ASN 76 HIS BE 78 THR HE 79 MET LEU 82 PHE
LEU 75 MET ASN 76 H? S BE 78 THR ILE 79 MET LEU 82 H? S
LEU 75 MET ASN 76 HiS SER 78 THR ILE 79 MET LEU 82 TYR
LEU 75 MET ASN 76 HIS BE 78 THR HE 79 THR LEU 82 PHE
LEU 75 MET ASN 76 HIS BE 78 THR LE 79 THR LEU 82 HIS
LEU 75 MET ASN 76 HIS BE 78 THR HE 79 THR LEU 82 TYR
LEU 75 MET ASN 76 HIS BE 78 THR HE 79 VAL LEU 82 PHE
LEU 75, ET ASN 76 HIS BE 78 THR HE 79 VAL LEU 82 H¡S
LEU 75 MET ASN 76 HIS BE 78 THR HE 79 VAL LEU 82 TYR
LEU 75 MET ASN 76 HIS BE 78 ARG HE 79 LEU LEU 82 PHE
LEU 75 MET ASN 76 H1S BE 78 ARG HE 79 LEU LEU 82 H? S
LEU 75 MET ASN 76 H? S SER 78 ARG 1LE 79 LEU LEU 82 TYR
LEU 75 MET ASN 76 HIS BE 78 ARG ILE 79 MET LEU 82 PHE
LEU 75 MET ASN 76 HIS BE 78 ARG HE 79 MET LEU 82 HIS
LEU 75 MET ASN 76 H1S SER 78 ARG ILE 79 MET LEU 82 TYR
LEU 75 MET ASN 76 HIS BE 78 ARG HE 79 THR LEU 82 PHE
LEU 75 MET ASN 76 HIS BE 78 ARG HE 79 TOR LEU 82 HIS
LEU 75 MET ASN 76 HIS BE 78 ARG ILE 79 TOR LEU 82 TYR
LEU 75 MET ASN 7 H5S SER 78 ARG HE 79 VAL LEU 82 PHE
LEU 75 MET ASN 76 H1S SER 78 ARG ILE 79 VAL LEU 82 HIS
LEU 75 MET ASN 76 HIS BE 78 ARG HE 79 VAL LEU 82 TYR
LEU 75 MET ASN 76 H? S BE 78 ASP HE 79 LEU LEU 82 PHE
LEU 75 MET ASN 76 HIS BE 78 ASP HE 79 LEU LEU 82 HIS
LEU 75 MET ASN 76 HIS BE 78 ASP HE 79 LEU LEU 82 TYR
LEU 75 MET ASN 76 HIS BE 78 ASP ILE 79 MET LEU 82 PHE
LEU 75 MET ASN 76 HIS BE 78 ASPLE 79 MET LEU 82 H1S
LEU 75 MET ASN 76 HIS BE 78 ASP ILE 79 MET LEU 82 TYR
LEU 75 MET ASN 76 HIS BE 78 ASP HE 79 TOR LEU 82 PHE
LEU 75 MET ASN 76 HiS SER 78 ASP HE 79 THR LEU 82 HIS
LEU 75 MET ASN 76 HIS BE 78 ASP HE 79 TOR LEU 82 TYR
LEU 75 MET ASN 76 HIS BE 78 ASP HE 79 VAL LEU 82 PHE
LEU 75 MET ASN 76 HiS SER 78 ASP HE 79 VAL LEU 82 HIS
LEU 75 MET ASN 76 HIS BE 78 ASP HE 79 VAL LEU 82 TYR
LEU 75 MET ASN 76 HIS BE 78 GLN HE 79 LEU LEU 82 PHE
LEU 75 MET ASN 76 HIS BE 78 GLN HE 79 LEU LEU 82 HIS
LEU 75 MET ASN 76 HIS BE 78 GLN HE 79 LEU LEU 82 TYR
LEU 75 MET ASN 76 HIS BE 78 GLN HE 79 MET LEU 82 PHE
LEU 75 MET ASN 76 H1S SER 78 GLN HE 79 MET LEU 82 HiS
LEU 75 MET ASN 76 HIS BE 78 GLN? LE 79 MET LEU 82 TYR
LEU 75 MET ASN 76 HIS SER 78 GLN HE 79 TOR LEU 82 PHE
LEU 75 MET ASN 76 HIS BE 78 GLN LE 79 TOR LEU 82 HIS
LEU 75 MET ASN 76 HIS BE 78 GLN HE 79 THR LEU 82 TYR
LEU 75 MET ASN 76 HIS BE 78 GLN HE 79 VAL LEU 82 PHE
LEU 75 MET ASN 76 HIS BE 78 GLN HE 79 VAL LEU 82 HIS
LEU 75 MET ASN 76 HIS BE 78 GLN HE 79 VAL LEU 82 TYR
LEU 75 MET ASN 76 H? S BE 78 HIS LE 79 LEU LEU 82 PHE
LEU 75 MET ASN 76 H? S BE 78 HIS HE 79 LEU LEU 82 HIS
LEU 75 MET ASN 76 HIS BE 78 HIS HE 79 LEU LEU 82 TYR
LEU 75 MET ASN 76 HIS BE 78 HIS ILE 79 MET LEU 82 PHE
LEU 75 MET ASN 76 HIS BE 78 H? S ILE 79 MET LEU 82 HIS
LEU 75 MET ASN 76 HIS BE 78 HIS HE 79 MET LEU 82 T? R
LEU 75 MET ASN 76 HIS BE 78 H? S HE 79 TOR LEU 82 PHE
LEU 75 MET ASN 76 HIS BE 78 H? S HE 79 TOR LEU 82 HIS
LEU 75 MET ASN 76 HIS BE 78 HIS HE 79 TOR LEU 82 TYR LEU 75 MET ASN 76 HIS BE 78 HIS HE "9 VAL LEU 82 PHE LEU 75 MET ASN 76 HiS SER 78 HIS LE '9 VAL LEU 82 H1S LEU 75 MET ASN 76 H1S BE 78 HIS HE 79 VAL LEU 82 TYR LEU 75 METASN 76 HIS BE 78 LYS LE 79 LEU LEE 82 PHE LEU 75 MET ASN 76 HIS BE 78 LYS LE LEU LEU 8 H1S LEU 75 MET ASN 76 HIS BE 78 LYS HE 79 LEU LEU 82 TYR LEU 75 METASN 76 HIS BE 78 LYS LE 79 MET LEU 82 PHE LEU 75 MET ASN 76 HIS BE 78 LYS LE 79 MET LEU 82 HIS LEU 75 MET ASN 76 H? S BE 78 LYS LE 79 MET LEU 82 TYR LEU 75 METASN 76 HIS BE 78 LYS LE 79 THR LEU 82 PHE LEU 75 METASN 76 HIS BE 78 LYS ILE 79 THR LEU 82 HIS LEU 75 METASN 76 H? S BE 78 LYS HE 79 THR LEU 82 TYR LEU 75 METASN 76 HIS BE 78 LYS LE 79 VAL LEU 82 PHE LEU 75 MET ASN 76 HIS BE 78 LYS LE 79 VAL LEU 82 H? S LEU 75 METASN 76 HIS BE 78 LYS LE 79 VAL LEU 82 TYR LEU 75 MET ASN 76 HIS BE 78 TYR HE 79 LEU LEU 82 PHE LEU 75 METASN 76 H? S BE 78 TYR LE 79 LEU LEU 82 HIS LEU 75 META SN 76 HIS BE 78 TYR ÍLE 79 LEU LEU 82 TYR LEU 75 MET ASN 76 H? S BE 78 TYR LE 79 MET LEU 82 PHE LEU 75 METASN 76 HIS BE 78 TYR ILE 79 MET LEU 82 HIS LEU 75 METASN 76 H? S BE 78 TYR? LE 79 MET LEU 82 TYR LEU 75 METASN 76 HIS BE 78 TYR INLE 79 TOR LEU 82 PHE LEU 75 MET ASN 76 HiS SER 78 TYR LE 79 TOR LEU 82 HIS
LEU 75 MET ASN 76 HIS BE 78 TYR 1LE 79 TOR LEU 82 TYR
LEU 75 MET ASN 76 H1S SER 78 TYR LE 79 VAL LEU 82 PHE
LEU 75 MET ASN 76 HIS BE 78 TYR HE 79 VAL LEU 82 HIS
LEU 75 MET ASN 76 HIS BE 78 TYR HE 79 VAL LEU 82 TYR
LEU 75 VAL ASN 76 HIS BE 78 ASN ILE 79 LEU LEU 82 PHE
LEU 75 VAL ASN 76 HIS BE 78 ASN ÍLE 79 LEU LEU 82 HIS
LEU 75 VAL ASN 76 HIS BE 78 ASN HE 79 LEU LEU 82 TYR
LEU 75 VAL ASN 76 H? S BE 78 ASN? LE 79 MET LEU 82 PHE
LEU 75 VAL ASN 76 HIS BE 78 ASN LE 79 MET LEU 82 HIS
LEU 75 VAL ASN 76 HTS SER 78 ASN LE 79 MET LEU 82 TYR
LEU 75 VAL ASN 76 HIS BE 78 ASN ÍLE 79 THR LEU 82 PHE
LEU 75 VAL ASN 76 HIS BE 78 ASN LE 79 TOR LEU 82 HIS
LEU 75 VAL ASN 76 HIS SER 78 ASN ILE 79 TOR LEU 82 TYR
LEU 75 VAL ASN 76 H? S SER 78 ASN ILE 79 VAL LEU 82 PHE
LEU 75 VAL ASN 76 H1S SER 78 ASN LE 79 VAL LEU 82 H1S
LEU 75 VAL ASN 76 H? S SER 78 ASN HE 79 VAL LEU 82 TYR
LEU 75 VAL ASN 76 HIS BE 78 THR HE 79 LEU LEU 82 PHE
LEU 75 VAL ASN 76 HIS BE 78 THR LE 79 LEU LEU 82 H? S
LEU 75 VAL ASN 76 HIS BE 78 TORILE 79 LEU LEU 82 T? R
LEU 75 VAL ASN 76 HIS BE 78 THR ILE 79 MET LEU 82 PHE
LEU 75 VAL ASN 76 HIS BE 78 THR ILE 79 MET LEU 82 H? S
LEU 75 VAL ASN 76 HIS BE 78 TOR ILE 79 MET LEU 82 TYR
LEU 75 VAL ASN 76 HIS BE 78 TORHILE 79 TOR LEU 82 PHE
LEU 75 VAL ASN 76 HIS BE 78 TOR 1LE 79 TOR LEU 82 HIS
LEU 75 VAL ASN 76 HIS BE 78 THR ÍLE 79 TOR LEU 82 TYR
LEU 75 VAL ASN 76 HtS SER 78 TOR ILE 79 VAL LEU 82 PHE
LEU 75 VAL ASN 76 HIS BE 78 TOR HE 79 VAL LEU 82 HIS
LEU 75 VAL ASN 76 H1S SER 78 TOR LE 79 VAL LEU 82 TYR
LEU 75 VAL ASN 76 H1S SER 78 ARG LE 79 LEU LEU 82 PHE
LEU 75 VAL ASN 76 H1S BE 78 ARG ÍLE 79 LEU LEU 82 H? S
LEU 75 VAL ASN 76 HIS BE 78 ARG HE 79 LEU LEU 82 TYR
LEU 75 VAL ASN 76 HIS BE 78 ARG HE 79 MET LEU 82 PHE
LEU 75 VAL ASN 76 HIS SER 78 ARG HE 79 MET LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 ARG ÍLE 79 MET LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 ARG ILE 79 TOR LEU 82 PHE LEU 75 VAL ASN 76 H? S SER 78 ARG ÍLE 79 THR LEU 82 H? S LEU 75 VAL ASN 76 H1S SER 78 ARG LE 79 TOR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 ARG LE 79 VAL LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 ARG LE 79 VAL LEU 82 HIS LEU 75 VAL ASN 76 HiS SER 78 ARG HE 79 VAL LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 ASP ILE 79 LEU LEU 82 PHE LEU 75 VAL ASN 76 H? S BE 78 ASP ILE 79 LEU LEU 82 HIS LEU 75 VAL ASN 76 H? S SER 78 ASP ILE 79 LEU LEU 82 T? R LEU 75 VAL ASN 76 H? S SER 78 ASP HE 79 MET LEU 82 PHE LEU 75 VAL ASN 76 HIS BE 78 ASP ILE 79 MET LEU 82 H? S LEU 75 VAL ASN 76 HIS BE 78 ASP HE 79 MET LEU 82 TYR LEU 75 VAL ASN 76 HIS BE 78 ASP? LE 79 THR LEU 82 PHE LEU 75 VAL ASN 76 H? S BE 78 ASP HE 79 THR LEU 82 HIS LEU 75 VAL ASN 76 HIS BE 78 ASP ILE 79 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS BE 78 ASP ÍLE 79 VAL LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 ASP ILE 79 VAL LEU 82 HIS LEU 75 VAL ASN 76 HJS SER 78 ASP ÍLE 79 VAL LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 GLN HE 79 LEU LEU 82 PHE LEU 75 VAL ASN 76 HIS BE 78 GLN HE 79 LEU LEU 82 H1S LEU 75 VAL ASN 76 HIS BE 78 GLN ILE 79 LEU LEU 82 TYR
LEU 75 VAL ASN 76 H1S SER 78 GLN JLE 79 MET LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 GLN HE 79 MET LEU 82 HIS LEU 75 VAL ASN 76 HiS SER 78 GLN HE 79 MET LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 GLN HE 79 THR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 GLN HE 79 TOR LEU 82 H1S LEU 75 VAL ASN 76 HIS SER 78 GLN HE 79 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 GLN HE 79 VAL LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 GLN HE 79 VAL LEU 82 HIS LEU 75 VAL ASN 76 H? S SER 78 GLN ÍLE 79 VAL LEU 82 T? R LEU 75 VAL ASN 76 H1S SER 78 HIS HE 79 LEU LEU 82 PHE LEU 75 VAL ASN 76 HIS BE 78 HIS HE 79 LEU LEU 82 H1S LEU 75 VAL ASN 76 HIS BE 78 HIS HE 79 LEU LEU 82 TYR
LEU 75 VAL ASN 76 HIS BE 78 HIS HE 79 MET LEU 82 PHE LEU 75 VAL ASN 76 HIS BE 78 H1S HE 79 MET LEU 82 HIS LEU 75 VAL ASN 76 H? S SER 78 HIS ILE 79 MET LEU 82 TYR LEU 75 VAL ASN 76 HiS SER 78 HIS HE 79 THR LEU 82 PHE LEU 75 VAL ASN 76 HiS SER 78 HIS HE 79 THR LEU 82 HIS LEU 75 VAL ASN 76 HIS BE 78 HIS HE 79 THR LEU 82 TYR LEU 75 VAL ASN 76 HiS SER 78 H? S HE 79 VAL LEU 82 PHE LEU 75 VAL ASN 76 HIS BE 78 HIS? LE 79 VAL LEU 82 HIS LEU 75 VAL ASN 76 HIS BE 78 HIS ILE 79 VAL LEU 82 TYR LEU 75 VAL ASN 76 HIS BE 78 LYS 1LE 79 LEU LEU 82 PHE LEU 75 VAL ASN 76 HIS BE 78 LYS HE 79 LEU LEU 82 HIS LEU 75 VAL ASN 76 H? S SER 78 LYS ILE 79 LEU LEU 82 TYR LEU 75 VAL ASN 76 H? S SER 78 LYS HE 79 MET LEU 82 PHE
LEU 75 VAL ASN 76 H1S SER 78 LYS HE 79 MET LEU 82 HiS LEU 75 VAL ASN 76 H1S SER 78 LYS HE 79 MET LEU 82 TYR LEU 75 VAL ASN 76 H? S SER 78 LYS HE 79 THR LEU 82 PHE LEU 75 VAL ASN 76 HIS BE 78 LYS HE 79 TOR LEU 82 H1S LEU 75 VAL ASN 76 HIS SER 78 LYS ILE 79 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 LYS ILE 79 VAL LEU 82 PHE LEU 75 VAL ASN 76 HiS SER 78 LYS HE 79 VAL LEU 82 HIS LEU 75 VAL ASN 76 H1S SER 78 LYS ÍLE 79 VAL LEU 82 TYR LEU 75 VAL ASN 76 HIS BE 78 TYR HE 79 LEU LEU 82 PHE LEU 75 VAL ASN 76 HIS BE "8 T? R JLE 79 LEU LEU 82 HiS LEU 75 VAL ASN 76 HIS BE 78 T? R? LE 79 LEU LEU 82 TYR LEU 75 VAL ASN 76 H1S SER 78 TYR ÍLE 79 MET LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 TYR LE 79 MET LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 TYR LE 79 MET LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 TYR HE 79 TOR LEU 82 PHE LEU 75 VAL ASN 76 HiS SER 78 TYR LE 79 THR LEU 82 HIS LEU 75 VAL ASN 76 HIS BE 78 TYR HE 79 TOR LEU 82 TYR LEU 75 VAL ASN 76 HIS BE 78 TYR ÍLE 79 VAL L EU 82 PHE LEU 75 VAL ASN 76 H? S SER 78 TYR ILE 79 VAL LEU 82 HIS LEU 75 VAL ASN 76 H? S SER 78 TYR JLE 79 VAL LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 ASN LE 79 LEU VAL 81 THR LEU 75 HE ASN 76 HIS SER 78 ASN LE 79 MET VAL 81 TOR LEU 75 LE ASN 76 H1S SER 78 ASN ILE 79 THR VAL 81 THR LEU 75 HE ASN 76 HIS SER 78 ASN HE 79 VAL VAL 81 THR LEU 75 HE ASN 76 H1S BE 78 THR? LE 79 LEU VAL 81 THR LEU 75 HE ASN 76 HIS BE 78 THR ÍLE 79 MET VAL 81 THR LEU 75 ÍLE ASN 76 H1S SER 78 THR HE 79 THR VAL 81 TOR LEU 75 LE ASN 76 HIS BE 78 THR ILE 79 VAL VAL 81 THR LEU 75 HE ASN 76 HiS SER 78 ARG HE 79 LEU VAL 81 TOR LEU 75 HE ASN 76 HERE BE 78 ARG ILE 79 MET VAL 81 THR
LEU 75 HE ASN 76 HIS BE 78 ARG HE 79 THR VAL 81 THR LEU 75? LE ASN 76 HIS BE 78 ARG ILE 79 VAL VAL 8! TOR LEU 75 ILE ASN 76 HIS BE 78 ASP? LE 79 LEU VAL 81 THR LEU 75 HE ASN 76 HiS BE 78 ASP JLE 79 MET VAL 81 THR LEU 75 HE ASN 76 HIS BE 78 ASP ILE 79 THR VAL 81 THR LEU 75 ILE ASN 76 HIS BE 78 ASP HE 79 VAL VAL 81 TOR LEU 75? LE ASN 76 HIS BE 78 GLN ILE 79 LEU VAL 1 TOR LEU 75 HE ASN 76 HIS BE 78 GLN HE 79 MET VAL 81 THR LEU 75 HE ASN 76 HIS BE 78 GLN ILE 79 THR VAL 81 TOR LEU 75? LE ASN 76 HIS SER 78 GLN HE 79 VAL VAL 81 THR LEU 75 HE ASN 76 HIS BE 78 HISEL 79 LEU VAL 81 THR LEU 75 HE ASN 76 H1S SER 78 HIS HE 79 MET VAL 81 THR LEU 75 HE ASN 76 HIS BE 78 HIS HE 79 THR VAL 81 THR
LEU 75 ILE ASN 76 HIS BE 78 HIS ILE 79 VAL VAL 81 THR LEU 75 ILE ASN 76 H? S SER 78 LYS ILE 79 LEU VAL 1 TOR LEU 75 HE ASN 76 H1S SER 78 LYS HE 79 MET VAL 81 THR LEU 75 HE ASN 76 H1S BE 78 LYS HE 79 TOR VAL 81 THR LEU 75 HE ASN 76 HIS BE 78 LYS HE 79 VAL VAL 81 TOR LEU 75 HE ASN 76 HIS BE 78 TYR? LE 79 LEU VAL 81 THR LEU 75 HE ASN 76 HIS BE 78 TYR HE 79 MET VAL 81 TOR LEU 75 HE ASN 76 HIS BE 78 TYR HE 79 THR VAL 81 THR LEU 75 HE ASN 76 H1S SER 78 TYR ÍLE 79 VAL VAL 81 TOR LEU 75 MET ASN 76 HIS SER 78 ASN? LE 79 LEU VAL 81 THR LEU 75 MET ASN 76 H1S SER 78 ASN HE 79 MET VAL 81 THR LEU 75 MET ASN 76 HIS SER 78 AS HE 79 THR VAL 81 TOR 'LEU 75 MET ASN 76 HIS SER 78 ASN HE 79 VAL VAL 81 THR
LEU 75 MET ASN 76 HIS BE 78 THR ILE 79 LEU VAL 81 THR LEU 75 MET ASN 76 HIS BE 78 THR HE 79 MET VAL 81 THR LEU 75 MET ASN 76 H1S SER 78 THR HE 79 TOR VAL 81 THR LEU 7 755 MMEETT AASSNN 76 HIS BE 78 TOR HE 79 VAL VAL 81 TOR LEU 75 MET ASN 76 HIS SER 78 ARG 1LE 79 LEU VAL 81 TOR LEU 75 MET ASN 76 HIS SER 78 ARG HE 79 MET VAL 81 THR LEU 75 MET ASN 76 H1S SER 78 ARG ILE 79 THR VAL 81 TOR LEU 75 MET ASN 76 HH S SER 78 ARG ILE 79 VAL VAL 81 TOR LEU 75 MET ASN 76 HIS BE 78 ASP HE 79 LEU VAL 81 THR LEU 75 MET ASN 76 HIS BE 78 ASP? LE 79 MET VAL 81 THR LEU 75 MET ASN 76 HIS BE 78 ASP ILE 79 TOR VAL 81 THR LEU 75 MET ASN 76 HtS SER 78 ASP 1LE 79 VAL VAL 81 THR LEU 75 MET ASN 76 H? S SER 78 GLN ILE 79 LEU VAL 81 TOR LEU 75 MET ASN 76 HIS SER 78 GLN? LE 79 MET VAL 8¡ TOR LEU 75 MET ASN 76 H1S SER 78 GLN ILE 79 THR VAL 81 THR LEU 75 MET ASN 76 HIS SER 78 GLN? LE 79 VAL VAL 81 TOR LEU 75 MET ASN 76 H? S BE 78 HIS ILE 79 LEU VAL 81 THR LEU 75 MET ASN 76 HIS BE 78 HIS HE 79 MET VAL 81 TOR LEU 75 MET ASN 76 HIS SER 78 HIS ILE 79 THR VAL 81 TOR LEU 75 MET ASN 76 H1S SER 78 H1S HE 79 VAL VAL St HR LEU 75 MET ASN 76 HIS SER 78 LYS ILE 79 LEU VAL 81 THR LEU 75 MET ASN 76 HIS BE 78 LYS ILE 79 MET VAL 81 TOR LEU 75 MET ASN 76 HIS BE 78 LYS HE 79 TOR VAL 81 THR LEU 75 MET ASN 76 H1S SER 78 LYS? LE 79 VAL VAL 81 TOR LEU 75 MET ASN 76 H? S BE 78 TYR HE 79 LEU VAL 8! TOR LEU 75 MET ASN 76 HIS SER 78 TYR HE 79 MET VAL 81 TOR LEU 75 MET ASN 76 HIS SER 78 TYR ILE 79 THR VAL 81 TOR LEU 75 MET ASN 76 HIS SER 78 TYR HE 79 VAL VAL 81 THR LEU 75 VAL ASN 76 HIS BE 78 ASN HE 79 LEU VAL 81 THR LEU 75 VAL ASN 76 HIS BE 78 ASN ILE 79 MET VAL 81 TOR LEU 75 VAL ASN 76 HIS SER 78 ASN HE 79 THR VAL 81 THR LEU 75 VAL ASN 76 HIS SER 78 ASN ILE 79 VAL VAL 81 THR LEU 75 VAL ASN 76 HIS SER 78 THR HE 79 LEU VAL 81 THR LEU 75 VAL ASN 76 HIS SER 78 THR? LE 79 MET VAL 81 TOR LEU 75 VAL ASN 76 HIS SER 78 THR ILE 79 THR VAL 81 TOR LEU 75 VAL ASN 76 HIS SER 78 THR ILE 79 VAL VAL 81 TOR LEU 75 VAL ASN 76 HIS SER 78 ARG? LE 79 LEU VAL 81 TOR LEU 75 VAL ASN 76 HIS SER 78 ARG ILE 79 MET VAL 81 THR LEU 75 VAL ASN 76 HIS BE 78 ARG HE 79 THR VAL 81 TOR LEU 75 VAL ASN 76 HIS BE 78 ARG HE 79 VAL VAL 81 THR LEU 75 VAL ASN 76 H? S BE 78 ASP HE 79 LEU VAL 81 THR LEU 75 VAL ASN 76 HIS BE 78 ASP HE 79 MET VAL 81 THR LEU 75 VAL ASN 76 HIS BE 78 ASP HE 79 THR VAL 81 THR LEU 75 VAL ASN 7 6 H1S SER 78 ASP ILE 79 VAL VAL 81 THR LEU 75 VAL ASN 76 HiS SER 78 GLN HE 79 LEU VAL 81 THR LEU 75 VAL ASN 76 HIS SER 78 GLN HE 7 ET VAL 81 THR LEU 75 VAL ASN 76 HIS SER 78 GLN HE 79 TOR VAL 81 THR LEU 75 VAL ASN 76 HiS SER 78 GLN HE 79 VAL VAL 81 TOR LEU 75 VAL ASN 76 HIS SER 78 HIS ILE 79 LEU VAL 81 THR LEU 75 VAL ASN 76 HIS SER 78 HIS ILE 79 MET VAL 81 THR LEU 75 VAL ASN 76 HIS SER 78 HIS HE 79 THR VAL 81 THR LEU 75 VAL ASN 76 H1S SER 78 HIS HE 79 VAL VAL 81 THR LEU 75 VAL ASN 76 HIS SER 78 LYS ILE 79 LEU VAL 81 THR LEU 75 VAL ASN 76 HIS BE 78 LYS ILE 79 MET VAL 81 THR LEU 75 VAL ASN 76 HiS SER 78 LYS HE 79 THR VAL 81 THR LEU 75 VAL ASN 76 HIS SER 78 LYS ILE 79 VAL VAL 81 TOR LEU 75 VAL ASN 76 HIS SER 78 TYR HE 79 LEU VAL 81 THR LEU 75 VAL ASN 76 HIS SER 78 TYR HE 79 MET VAL 81 THR LEU 75 VAL ASN 76 H? S SER 78 TYR HE 79 THR VAL 81 THR LEU 75 VAL ASN 76 HIS SER 78 TYR ILE 79 VAL VAL 81 THR TABLE 7 Sextuple substitution variants
LEU 75 ILE ASN 76 HIS BE 78 ASN ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75ILEASN 76 HIS SER 78 ASN LE 79 LEU VAL 81 THRLEU 82 H1S LEU 75ILEASN 76 HIS SER 78 ASN HE 79 LEU VAL 81 THRLEU 82 TYR LEU 751LE ASN 76 HIS BE 78 ASN HE 79 MET VAL 81 THR LEU 82 PHE LEU 75ILEASN 76 HIS SER 78 ASN ILE 79 MET VAL 81 THRLEU 82 HIS LEU 75 ILE ASN 76 HIS BE 78 ASN HE 79 MET VAL 81 THR LEU 82 TYR LEU 75 LE ASN 76 HIS BE 78 ASN LE 79 THR VAL 81 TOR LEU 82 PHE LEU 75ILEASN 76 HIS BE 78 ASN ILE 79 TOR VAL 8! THRLEU 82 HIS LEU 75ILEASN 76HISSER 78 ASN HE 7 TORVAL 81 TORLEU 82T? R LEU 75ILEASN 76HISSER 78 ASN HE 79 VAL VAL 81 THRLEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 ASN HE 79 VAL VAL 81 TOR LEU 82 H1S LEU 75 ILE ASN 76 HIS BE 78 ASN iLE 79 VAL VAL 81 THRLEU 82 TYR LEU 75 ILE ASN 76 HIS BE 78 THR HE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS BE 78 THR ILE 79 LEU VAL 1 THR LEU 82 HIS LEU 75ILEASN 76H1SSER 78THRILE 79 LEU VAL 8! THRLEU 82 TYR LEU 75ILEASN 76 H? S BE 78 THR HE 79 MET VAL 81 TORLEU 82 PHE LEU 75ILEASN 76HISSER 78THR1LE 79 MET VAL 81 TH LEU 82 HiS LEU 75 ILE ASN 76 HIS BE 78 THR HE 79 MET VAL 81 TOR LEU 82 TYR LEU 75ILEASN 76 HIS BE 78THRILE 79 THR VAL 81 THRLEU 82 PHE LEU 75ILEASN 76 HIS BE 78THRILE 79 THR VAL 81 TH LEU 82 HIS LEU 75? LE ASN 7 HISSER 78THRILE 79 THR VAL 81 THRLEU 82TYR LEU 75ILEASN 76HISSER 78 THR HE 79 VAL VAL 81 THRLEU 82 PHE LEU 75ILEASN 76HISSER 78 THR HE 79 VAL VAL 81 TUR LEU 82 HIS LEU 75ILEASN 76HISSER 78TH ILE 79 VAL VAL 81 TH LEU 82 TYR LEU 75? LE ASN 76HISSER 78 ARG HE 79 LEU VAL 81 TORLEU 82 PHE LEU 75 ILE ASN 76 HIS BE 78 ARG ILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76 HIS BE 78 ARG ILE 79 LEU VAL 81 TOR LEU 82 TYR LEU 75 HE ASN 76 HiS SER 78 ARG HE 79 MET VAL 81 TORLEU 82 PHE LEU 75 ILE ASN 76 HIS BE 78 ARG HE 79 MET VAL 81 TOR LEU 82 HIS LEU 75 ILE ASN 76 HIS BE 78 ARG HE 79 MET VAL 81 THR LEU 82 TYR LEU 75 ILE ASN 76 HIS BE 78 ARG HE 79 TOR VAL 81 T HR LEU 82 PHE LEU 75 HE ASN 76HISSER 78 ARG ÍLE 79 TOR VAL 81 TORLEU 82 HIS LEU 75 ILE ASN 76 HIS BE 78 ARG HE 79 THR VAL 81 THR LEU 82 TYR LEU 75ILEASN 76HISSER 78ARGILE 79 VAL VAL 81THRLEU 82 PHE LEU 75 HE ASN 76 H? S BE 78 ARG HE 79 VAL VAL 81 THRLEU 82 HIS LEU 75 HE ASN 76H1SSER 78 ARG HE 79 VAL VAL 81 TORLEU 82 TYR LEU 75 ILE ASN 76 H? S BE 78 ASP HE 79 LEU VAL 81 THR LEU 82 PHE LEU 75ILEASN 76HISSER 78 ASP ILE 79 LEU VAL 81 TH LEU 82 H1S LEU 75 HE ASN 7 HISSER 78 ASP HE 79 LEU VAL 81 THRLEU 82 TYR LEU 7SHE SN 76 HIS BE 78ASPILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76HISSER 78 ASP HE 79 MET VAL 81 TO LEU 82HIS LEU 75 HE ASN 76 HIS BE 78 ASP HE 79 MET VAL 81 THR LEU 82 TYR LEU 75 HE ASN 76 HIS BE 78 ASP HE 79 THR VAL 81 TH LEU 82 PHE LEU 75 HE ASN 76 HIS BE 78 ASP HE 79 THR VAL 81 THR LEU 82 H? S LEU 75ILEASN 76HISSER 78 ASPÃLE 79 THR VAL 81 THR EU 82TYR LEU 75 HE ASN 76 HiS SER 78 ASP HE 79 VAL VAL 81 THR EU 82 PHE LEU 75 HE ASN 76HISSER 78 ASP HE 79 VAL VAL 8ITORL EU 82HIS LEU 75 HE ASN 76 HIS BE 78 ASP HE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 HE ASN 76HISSER 78 GLN ILE 79 LEU VAL 81 TUR LEU 82 PHE LEU 75 HE ASN 76HISSER 78 GLN HE 79 LEU VAL 81 THRLEU 82H1S LEU 75 ILE ASN 76 H1S SER 78 GLN HE 79 LEU VAL 81 THR LEU 82 TYR LEU 75E.EASN 76HISSER 78 GLN HE 79 MET VAL 81 THR EU 82 PHE LEU 75ILEASN 76 HIS SER 78 GLN HE 79 MET VAL 81 TORLEU 82 HJS LEU 75 HE ASN 76HISSER 78 GLN HE 79 ETVAL 81 THRLEU 82 TYR LEU 75 ÍLE ASN 76 HIS BE 78 GLN HE 79THRVAL 8! TH LEU 82 PHE LEU 75 HE ASN 76 HIS BE 78 GLN HE 79 THR VAL 81 THR LEU 82 HIS LEU 75 LE ASN 76 HIS BE 78 GLN ILE 79 THR VAL 81 THR LEU 82 T? R LEU 75 ILE ASN 76 HIS TO BE 78 GLN LE 79 VAL VAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 GLN HE 79 VAL VAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 GLN ILE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 LE ASN 76 HIS BE 78 HIS ILE 79 LEU VAL 81 TOR LEU 82 PHE LEU 75 LE ASN 76 HIS BE 78 H? S 1LE 79 LEU VAL 81 TOR LEU 82 HiS LEU 75 ÍLE ASN 76 HIS BE 78 HJS HE 79 LEU VAL 81 TOR LEU 82 TYR LEU 75 HE ASN 76 HIS BE 78 HfS HE 79 MET VAL 81 TOR LEU 82 PHE LEU 75 ÍLE ASN 76 H? S BE 78 HIS HE 79 MET VAL 81 THR LEU 82 H1S LEU 75 HE ASN 76 H? S BE 78 HIS HE 79 MET VAL 81 THR LEU 82 T? R LEU 75 HE ASN 76 HIS BE 78 HIS HE 79 TOR VAL 81 TOR LEU 82 PHE LEU 75 ILE ASN 76 HIS BE 78 HIS HE 79 TOR VAL 81 THR LEU 82 HIS LEU 75 HE ASN 76 HIS BE 78 HIS HE 79 TOR VAL 81 THR LEU 82 TYR LEU 75 LE ASN 76 HIS BE 78 HIS ILE 79 VAL VAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS BE 78 HIS ILE 79 VAL VAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76 HIS BE 78 HIS HE 79 VAL VAL 8¡ THR LEU 82 TYR
LEU 75 1LE ASN 76 HIS BE 78 LYS HE 79 LEU VAL 81 TOR LEU 82 PHE LEU 75 HE ASN 76 HIS BE 78 LYS ÍLE 79 LEU VAL 81 THR LEU 82 H? S LEU 75 ILE ASN 76 HIS BE 78 LYS HE 79 LEU VAL 81 THR LEU 82 T? R LEU 75 HE ASN 76 HIS BE 78 LYS ILE 79 MET VAL 81 TOR LEU 82 PHE LEU 75 HE ASN 76 HIS BE 78 LYS ILE 79 MET VAL 81 TOR LEU 82 HIS LEU 75 1LE ASN 76 HIS BE 78 LYS ILE 79 MET VAL 81 TOR LEU 82 TYR LEU 75 LE ASN 76 H1S SER 78 LYS ILE 79 TOR VAL 81 THR LEU 82 PHE LEU 75 LE ASN 76 H? S SER 78 LYS ILE 79 TOR VAL 8 THR LEU 82 HIS LEU 75 HE ASN 76 HIS BE 78 LYS HE 79 THR VAL 81 TOR LEU 82 TYR LEU 75 HE ASN 76 HIS BE 78 LYS ILE 79 VAL VAL 81 THR LEU 82 PHE LEU 75 HE ASN 76 HIS BE 78 LYS HE 79 VAL VAL 81 THR LEU 82 HIS LEU 75 HE ASN 76 HIS BE 78 LYS HE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 HE ASN 76 HIS BE 78 TYR ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 HE ASN 76 HERE BE 78 TYR HE 79 LEU VAL 81 THR LEU 82 H1S LEU 75 HE ASN 76 HIS BE 78 TYR HE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 HE ASN 76 HIS BE 78 TYR ÍLE 79 MET VAL 81 THR LEU 82 PHE LEU 75 HE ASN 76 HIS BE 78 TYR 1LE 79 MET VAL 81 THR LEU 82 HIS LEU 75 HE ASN 76 HIS BE 78 TYR ILE 79 MET VAL 81 TOR LEU 82 TYR LEU 75 HE ASN 76 HIS BE 78 TYR HE 79 TOR VAL 81 TOR LEU 82 PHE LEU 75 HE ASN 76 H? S BE 78 TYR ILE 79 TOR VAL 81 THR LEU 82 H? S
LEU 75 HE ASN 76 HIS BE 78 TYR HE 79 THR VAL 81 TOR LEU 82 TYR LEU 75 HE ASN 76 HIS BE 78 TYR HE 79 VAL VAL 81 THR LEU 82 PHE LEU 75 HE ASN 76 HIS BE 78 TYR HE 79 VAL VAL 81 TOR LEU 82 HIS LEU 75 HE ASN 76 HIS BE 78 TYR? LE 79 VAL VAL 81 TOR LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 ASN HE 79 LEU VAL 81 TOR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 ASN HE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 ASN ILE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 MET ASN 76 H1S SER 78 ASN ILE 79 MET VAL 81 TOR LEU 82 PHE LEU 75 MET ASN 76 HIS BE 78 ASN ILE 79 MET VAL 81 TOR LEU 82 HiS LEU 75 MET ASN 76 HIS SER 78 ASN HE 79 MET VAL 8 i THR LEU 82 TYR LEU 75 MET ASN 76 HIS BE 78 ASN ILE 79 THR VAL 81 TOR LEU 82 PHE LEU 75 MET ASN 7 HIS SER 78 ASN HE 79 THR VAL If THR LEU 82 H1S LEU 75 MET ASN 76 H1S SER 78 ASN HE 79 TOR VAL Si TOR LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 ASN HE 79 VAL VAL 81 TOR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 ASN ILE 79 VAL VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HIS S ER 78 ASN HE 79 VAL VAL 81 TOR LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 TOR HE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 TOR HE 79 LEU VAL 81 TOR LEU 82 HIS LEU 75 MET ASN 76 HIS BE 78 TOR HE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 MET ASN 76 HIS BE 78 TOR HE 79 MET VAL 81 TH LEU 82 PHE 5
LEU 75 MET ASN 76 HIS BE 78 TOR LE 79 MET VAL 81 TOR LEU 82 HIS
LEU 75 MET ASN 76 H1S SER 78 THR HE 79 MET VAL 81 THR LEU 82 TYR
LEU 75 MET ASN 76 HIS BE 78 TOR HE 79 TOR VAL 81 TOR LEU 82 PHE
LEU 75 MET ASN 76 HIS BE 78 TOR HE 79 TOR VAL 81 TOR LEU 82 HJS
LEU 75 MET ASN 76 HJS SER 78 THR HE 79 THR VAL 81 THR LEU 82 TYR
LEU 75 MET ASN 76 HIS BE 78 TOR HE 79 VAL VAL 81 THR LEU 82 PHE
LEU 75 MET ASN 76 HiS SER 78 THR HE 79 VAL VAL 81 THR LEU 82 HIS
LEU 75 MET ASN 76 HIS BE 78 TOR HE 79 VAL VAL 81 TOR LEU 82 TYR
LEU 75 MET ASN 76 HIS BE 78 ARG ILE 79 LEU VAL 81 TOR LEU 82 PHE
LEU 75 MET ASN 76 H1S SER 78 ARG HE 79 LEU VAL 81 TOR LEU 82 HIS
LEU 75 MET ASN 76 HIS BE 78 ARG? LE 79 LEU VAL 81 TOR LEU 82 TYR
LEU 75 MET ASN 76 HIS BE 78 ARG ILE 79 MET VAL 81 TOR LEU 82 PHE
LEU 75 MET ASN 76 H1S SER 78 ARG HE 79 MET VAL 81 TOR LEU 82 HIS
LEU 75 MET ASN 76 HIS BE 78 ARG HE 79 MET VAL 81 THR LEU 82 TYR
LEU 75 MET ASN 76 H? S SER 78 ARG ILE 79 THR VAL 81 TOR LEU 82 PHE
LEU 75 MET ASN 7 HIS BE 78 ARG HE 7 TOR VAL 81 TOR LEU 82 HJS
LEU 75 MET ASN 76 HIS BE 78 ARG HE 79 TOR VAL 81 THR LEU 82 TYR
LEU 75 MET ASN 76 HIS BE 78 ARG? LE 79 VAL VAL 81 TOR LEU 82 PHE
LEU 75 MET ASN 76 HIS BE 78 ARG HE 79 VAL VAL 81 THR LEU 82 H? S
LEU 75 MET ASN 76 H? S BE 78 ARG HE 79 VAL VAL 8! TOR LEU 82 TYR
LEU 75 MET ASN 76 HIS BE 78 ASP HE 79 LEU VAL 81 TOR LEU 82 PHE
LEU 75 MET ASN 76 HIS BE 78 ASP HE 79 LEU VAL 81 THR LEU 82 HIS
LEU 75 MET ASN 76 HIS BE 78 ASP HE 79 LEU VAL 81 TH LEU 82 TYR
LEU 75 MET ASN 76 H? S BE 78 ASP HE 79 MET VAL 81 THR LEU 82 PHE
LEU 75 METASN 76 HIS BE 78 ASP HE 79 MET VAL 81 TOR LEU 82 H1S
LEU 75 MET ASN 76 HIS BE 78 ASP HE 79 MET VAL 81 TOR LEU 82 TYR
LEU 75 MET ASN 76 HIS BE 78 ASP ILE 79 TOR VAL 81 TOR LEU 82 PHE
LEU 75 MET ASN 76 HIS BE 78 ASP? LE 79 THR VAL 81 TOR LEU 82 H? S
LEU 75 MET ASN 76 HIS BE 78 ASP HE 79 THR VAL 81 TOR LEU 82 T? R
LEU 75 MET ASN 76 HIS BE 78 ASP HE 79 VAL VAL 81 THR LEU 82 PHE
LEU 75 MET ASN 76 HIS BE 78 ASP HE 79 VAL VAL 81 TH LEU 82 HIS
LEU 75 MET ASN 76 H1S SER 78 ASP HE 79 VAL VAL 81 TOR LEU 82 T? R
LEU 75 MET ASN 76 HIS BE 78 GLN ILE 79 LEU VAL 81 THR LEU 82 PHE
LEU 75 MET ASN 76 HIS BE 78 GLN HE 79 LEU VAL 81 TOR LEU 82 HIS
LEU 75 MET ASN 76 HIS SER 78 GLN HE 79 LEU VAL 81 TOR LEU 82 TYR
LEU 75 MET ASN 76 H? S BE 78 GLN HE 79 MET VAL 81 THR LEU 82 PHE
LEU 75 MET ASN 76 HIS BE 78 GLN HE 79 MET VAL 81 THR LEU 82 HIS
LEU 75 MET ASN 76 HIS SER 78 GLN ILE 79 MET VAL 81 TOR LEU 82 TYR
LEU 75 MET ASN 76 HiS SER 78 GLN? LE 79 THR VAL 81 TOR LEU 82 PHE
LEU 75 MET ASN 76 HIS BE 78 GLN ILE 79 TOR VAL 81 TOR LEU 82 HIS
LEU 75 MET ASN 76 HIS BE 78 GLN HE 79 TOR VAL 81 THR LEU 82 TYR
LEU 75 MET ASN 7 H1S SER 78 GLN HE 79 VAL VAL S1 TOR LEU 82 PHE
LEU 75 MET ASN 76 HIS SER 78 GLN ILE 79 VAL VAL 81 TOR LEU 82 HIS
LEU 75 MET ASN 76 HIS SER 78 GLN? LE 79 VAL VAL 81 TOR LEU 82 TYR
LEU 75 MET ASN 76 H1S BE 78 HIS HE 79 LEU VAL 81 TOR LEU 82 PHE
LEU 75 MET ASN 76 HIS BE 78 HIS? LE 79 LEU VAL 81 TOR LEU 82 H? S
LEU 75 MET ASN 76 HIS BE 78 HIS? LE 79 LEU VAL 81 TOR LEU 82 TYR
LEU 75 MET ASN 76 HIS BE 78 HIS ILE 79 MET VAL 81 TOR LEU 82 PHE
LEU 75 MET ASN 76 HIS BE 78 HIS HE 79 MET VAL 81 TOR LEU 82 H? S
LEU 75 MET ASN 76 HIS BE 78 HIS HE 79 MET VAL 81 TOR LEU 82 TYR
LEU 75 MET ASN 76 HIS BE 78 HIS ILE 79 THR VAL 81 TOR LEU 82 PHE
LEU 75 MET ASN 76 HIS BE 78 HIS HE 79 THR VAL 81 TOR LEU 82 HíS
LEU 75 MET ASN 76 HIS BE 78 HIS HE 79 THR VAL 81 TOR LEU 82 TYR
LEU 75 MET ASN 76 HIS BE 78 HIS HE 79 VAL VAL 81 THR LEU 82 PHE
LEU 75 MET ASN 76 H? S BE 78 H? S HE 79 VAL VAL 81 TOR LEU 82 HIS
LEU 75 MET ASN 76 HiS SER 78 HIS ILE 79 VAL VAL 81 TOR LEU 82 TYR LEU 75 MET ASN 76 HIS SER 7S LYS ÍLE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 LYS 1LÉ 79 LEU VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HIS BE 78 LYS ÍLE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 MET ASN 76 HiS SER 78 LYS HE 79 MET VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HIS BE 78 LYS HE 79 MET VAL 81 THR LEU 82 HIS LEU 75 MÉT ASN 7 HIS BE 78 LYS ÍLE 79 MET VAL 81 THR LEU 82 TYR LEU 75 MET ASN 76 H¡S SER 78 LYS LE 79 TOR VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HIS BE 78 LYS HE 79 TOR VAL 8¡ THR LEU 82 H1S LEU 75 MET ASN 76 HIS BE 78 LYS HE 79 TOR VAL 81 THR LEU 82 TYR LEU 75 MET ASN 76 H¡S SER 78 LYS LE 79 VAL VAL SJ TOR LEU 82 PHE LEU 75 MET ASN 76 HIS BE 78 LYS HE 79 VAL VAL 81 TOR LEU 82 HIS LEU 75 MET ASN 7 HIS SER 78 LYS HE 79 VAL VAL 81 TOR LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 TYR ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HIS BE 78 TYR HE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HIS BE 78 TYR HE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 MET ASN 76 HIS BE 78 TYR INE 79 MET VAL 81 TOR LEU 82 PHE LEU 75 MET ASN 76 HIS BE 78 TYR HE 79 MET VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 H? S BE 78 TYR ILE 79 MET VAL 81 THR LEU 82 T? R LEU 75 MET ASN 76 HIS BE 78 TYR HE 79 TOR VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 H1S SER 78 TYR HE 79 TOR VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 H1S SER 78 TYR HE 79 THR VAL 81 THR LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 TYR ILE 79 VAL VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HiS SER 78 TYR ILE 79 VAL VAL 81 THR LEU 82 H1S LEU 75 MET ASN 76 HIS SER 78 TYR? LE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 ASN HE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 HIS BE 78 ASN HE 79 LEU VAL 81 TOR LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 ASN HE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 ASN ILE 79 MET VAL 81 TOR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 ASN? LE 79 MET VAL 81 THR LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 ASN HE 79 MET VAL 81 THR LEU 82 TYR LEU 75 VAL ASN 7 HIS SER 78 ASN HE 79 TOR VAL 81 TUR LEU 82 PHE LEU 75 VAL ASN 76 H? S SER 78 ASN HE 79 TOR VAL 81 THR LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 ASN ILE 79 THR VAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 ASN HE 79 VAL VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 ASN? LE 79 VAL VAL 81 TOR LEU 82 H? S LEU 75 VAL ASN 76 HIS BE 78 ASNILE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 TOR ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 TOR LE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 THR HE 79 LEU VAL 81 TOR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 THR? LE 79 MET VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 HiS SER 78 T HR? LE 79 MET VAL 1 THR LEU 82 HIS LEU 75 VAL ASN 76 HIS BE 78 THR HE 79 MET VAL 8 THR LEU 82 T? R LEU 75 VAL ASN 76 HERE BE 78 THR HE 79 TOR VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 HIS BE 78 TOR HE 79 TOR VAL 81 THR LEU 82 H? S LEU 75 VAL ASN 76 HIS SER 78 THR HE 79 TOR VAL 81 TOR LEU 82 TYR LEU 75 VAL ASN 7 HIS SER 78 THR HE 79 VAL VAL 81 TOR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 TOR HE 79 VAL VAL 81 TOR LEU 82 H1S LEU 75 VAL ASN 76 H1S SER 78 THR HE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 ARG HE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 ARG ILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 VAL ASN 76 HiS SER 78 ARG ILE 79 LEU VAL 81 TOR LEU 82 TYR LEU 75 VAL ASN 76 H? S SER 78 ARG HE 79 MET VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 H1S SER 78 ARG ILE 79 MET VAL 81 THR LEU 82 HIS LEU 75 VAL ASN 76 H? S SER 78 ARG HE 79 MET VAL 8 i THR LEU 82 TYR LEU 75 VAL ASN 76 HIS BE 78 ARG HE 79 TOR VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 HIS BE 78 ARG? LE 79 TOR VAL 81 TOR LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 ARG HE 79 TOR VAL 81 TOR LEU 82 TYR
LEU 75 VAL ASN 76 HIS BE 78 ARG LE 9 VAL VAL 81 THR LEU 82 PHE
LEU - > 5 VAL ASN 76 HIS BE 78 ARG HE 79 VAL VAL 81 TOR LEU 82 H? S
LEU 75 VAL ASN 76 HIS BE 78 ARG HE 79 VAL VAL 81 THRLEU 82 TYR
LEU 75 VAL ASN 76 HiS SER 78 ASP LE 79 LEU VAL 81 THR LEU 82 PHE
LEU 75 VAL ASN 76HISSER 78 ASP HE 79 LEU VAL 81 THRLEU 82 HIS
LEU 75 VAL ASN 76 HIS BE 78 ASP HE 79 LEU VAL 81 TORLEU 82 TYR
LEU 75 VAL ASN 76 HIS BE 78 ASP HE 79 MET VAL Yes TOR LEU 82 PHE
LEU 75 VAL ASN 76 HIS BE 78 ASP LE 79 MET VAL 81 TOR LEU 82 HIS
LEU 75 VAL ASN 76HISSER 78 ASP HE 79 MET VAL 8 THRLEU 82 TYR
LEU 75 VAL ASN 76 HIS BE 78 ASP LE 79 THR VAL 81 THR LEU 82 PHE
LEU 75 VAL ASN 76 HIS BE 78 ASP HE 79 TOR VAL 81 THR LEU 82 H? S
LEU 75 VAL ASN 76 HIS BE 78 ASP HE 7 THRVAL 81 TH LEU 82 T? R
LEU 75 VAL ASN 76 HIS BE 78 ASP LE 79 VAL VAL 81 THR LEU 82 PHE
LEU 75 VAL ASN 76 HIS BE 78 ASP ÍLE 79 VAL VAL 81 TOR LEU 82 HIS
LEU 75 VAL ASN 76 HIS BE 78 ASP LE 79 VAL VAL 81 THR LEU 82 TYR
LEU 75 VAL ASN 76 HIS BE 78 GLN HE 79 LEU VAL 81 THR LEU 82 PHE
LEU 75 VAL ASN 76HISSER 78 GLN HE 79 LEU VAL 8 THRLEU 82 HIS
LEU 75 VAL ASN 76 HIS BE 78 GLN HE 79 LEU VAL 81TORLEU 82 TYR
LEU 75 VAL ASN 76 HIS BE 78 GLN HE 79 MET VAL 81 TOR LEU 82 PHE
LEU 75 VAL ASN 76HISSER 78 GLN HE ^ MET VAL 81 TORLEU 82 HIS
LEU 75 VAL ASN 76 HIS BE 78 GLN HE 79 MET VAL 8! TOR LEU 82 TYR
LEU 75 VAL ASN 7 HISSER 78 GLN HE 79 THR VAL 81 TORLEU 82 PHE
LEU 75 VAL ASN 76 HIS BE 78 GLN HE 79 THR VAL 81TORLEU 82 HIS
LEU 75 VAL ASN 76 H1S SER 78 GLN 1LE 79 THR VAL 81 THR LEU 82 TYR
LEU 75 VAL ASN 76 H? S SER 78 GLN ILE 79 VAL VAL 81 TOR LEU 82 PHE
LEU 75 VAL ASN 76HISSER 78 GLN HE 79 VAL VAL 81THRLEU 82 HiS
LEU 75 VAL ASN 76 HIS SER 78 GLN HE 79 VAL VAL 81 TOR LEU 82 TYR
LEU 75 VAL ASN 76HISSER 78HISHE 79 LEU VAL 81 THRLEU 82 PHE
LEU 75 VAL ASN 76 HIS BE 78 HIS HE 79 LEU VAL 81 THR EU 82 HIS
LEU 75 VAL ASN 76HISSER 78 H? S HE 79 LEU VAL 81 TO LEU 82 TYR
LEU 75 VAL ASN 76 HIS BE 78 HIS HE 79 MET VAL 81 THR LEU 82 PHE
LEU 75 VAL ASN 76 HIS BE 78 H1S HE 79 MET VAL 81 THRLEU 82 HIS
LEU 75 VAL ASN 76 HIS BE 78 HIS HE 79 MET VAL 81 THR LEU 82 T? R
LEU 75 VAL ASN 76 HIS BE 78 HIS HE 79 TOR VAL 81 TOR LEU 82 PHE
LEU 75 VAL ASN 76HISSER 78 H? S HE 79THRVAL 81 TORLEU 82 HIS
LEU 75 VAL ASN 76HISSER 78 HIS HE 79 THR VAL 81 THRLEU 82 T? R
LEU 75 VAL ASN 76 HIS BE 78 HIS HE 79 VAL VAL 81 TOR LEU 82 PHE
LEU 75 VAL ASN 76 HIS BE 78 HIS HE 79 VAL VAL 81 THR LEU 82 HIS
LEU 75 VAL ASN 76HISSER 78 HIS HE 79 VAL VAL 81 THRLEU 82 TYR
LEU 75 VAL ASN 76HISSER 78 LYS HE 79 LEU VAL 81 TORLEU 82 PHE
LEU 75 VAL ASN 76 HIS BE 78 LYS HE 79 LEU VAL 81 TOR LEU 82 H? S
LEU 75 VAL ASN 76 HiS SER 78 LYS HE 79 LEU VAL 81 TORLEU 82 TYR
LEU 75 VAL ASN 76HISSER 78 LYS HE 79 MET VAL 81 TORLEU 82 PHE
LEU 75 VAL ASN 76 HIS BE 78 LYS HE 79 MET VAL 81 TOR LEU 82 HIS
LEU 75 VAL ASN 76HISSER 78 LYS HE 79 MET VAL 81 TORLEU 82 TYR
LEU 75 VAL ASN 76HISSER 78 LYS HE 7 TORVAL 81 THRLEU 82 PHE
LEU 75 VAL ASN 76 HIS BE 78 LYS HE 79 THR VAL 81 THR LEU 82 HIS
LEU 75 VAL ASN 76HISSER 78 LYS HE 79 TOR VAL 8 i THR LEU 82 TYR
LEU 75 VAL ASN 7 HISSER 78 LYS HE 79 VAL VAL 81 TORLEU 82 PHE
LEU 75 VAL ASN 76 HIS BE 78 LYS ILE 79 VAL VAL 81 THR LEU 82 HIS
LEU 75 VAL ASN 76 HIS SER 78 LYS ILE 79 VAL VAL 81 TOR LEU 82 TYR
LEU 75 VAL ASN 76 HIS BE 78 TYR LE 79 LEU VAL 81 THR LEU 82 PHE
LEU 75 VAL ASN 76 HIS BE 78 T? R ILE 79 LEU VAL 81 TOR LEU 82 HIS
LEU 75 VAL ASN 76HISSER 78 TYR HE 79 LEU VAL 8! THRLEU 82 TYR
LEU 75 VAL ASN 76 HIS BE 78 TYR HE 79 MET VAL 81 TORLEU 82 PHE LEU 75 VAL ASN 76 HIS BE 78 TYR ILE 79 MET VAL 81 THRLEU 82 HIS
LEU 75 VAL ASN 76 HIS BE 78 TYR ÍLE 79 MET VAL 81 THRLEU 82 TYR
LEU 75 VAL ASN 76 H? S BE 78 TYR ÍLE 79 THR VAL 8 i THRLEU 82 PHE
LEU 75 VAL ASN 76 H? S BE 78 TYR? LE 79 THR VAL 81 THRLEU 82HIS
LEU 75 VAL ASN 76 H1S SER 78 TYR HE 79 THR VAL 81 THRLEU 82TYR 75 VAL ASN 76 HIS SER 78 TYR 1LE 79 VAL VAL 81 THRLEU 82PHE
LEU 75 VAL ASN 76 HIS SER 78 TYR ILE 79 VAL VAL 81 TOR LEU 82H1S LEU 75 VAL ASN 76 H1S SER 78 TYR HE 79 VAL VAL 81 THRLEU 8 TYR TABLE 8 Variants of a single substitution LEU 82 PHE LEU 82 HIS VAL Si THR HE 79 LEU ILE 79 MET HE 79 TUR SER 78 ASN SER 78THR ASN 76HIS LEU 75 HE LEU 75 MET TABLE 9 Variants of double substitution VAL 8ITHRLEU 82 PHE VAL 81 THRLEU 82 HIS HE 79 LEU LEU 82 PHE HE 79 LEU LEU 82 HIS HE 79 MET LEE 82 PHE ILE 79 MET LEU 82 HIS? LE 79Í? RLEU 82 PHE HE 79 THR LEU 82 HiS HE 79 LEU VAL 81 THR HE 79 MET VAL 81 THR HE 79 THR VAL 81 THR SER 78 ASN LEU 82 PHE SER 78 ASN LEU 82 HIS BE 78 TUR LEU 82 PHE BE 78 THR LEU 82 HIS BE 78 ASN VAL 81 THR BE 78THRVAL 81 THR BE 78 ASN? LE 79 LEU BE 78 ASN HE 79 MET BE 78ASNILE 79 THR BE 78 THR ÍLE 79 LEU SER 78 THR HE 79 MET BE 78 THR HE 79 THR ASN 7 HISLEU 82 PHE ASN 76HISLEU 82 H? S ASN 76HISVAL 81 THR ASN 76 H1S ILE 79 LEU ASN 76 HIS LE 79 MET ASN 76 HiS HE 79 THR ASN 76 H1S SER 78 ASN ASN 76 H? S SER 78 THR LEU 75 ILE LEU 82 PHE LEU 75 ILE LEU 8 HIS LEU 75 MET LEU 82 PHE LEU 75 MET LEU 82 HIS LEU 75ILEVAL 81 THR LEU 75 MET VAL 8 THR LEU 75 ILE ILE 79 LEU LEU 75 ILE HE 79 MET LEU 75 ILE ILE 79 THR LEU 75 MET ILE 79 LEU LEU 75 MET HE 79 MET LEU 75 METILE 79 THR LEU 75 HE BE 78 ASN LEU 75 ILE SER 78 THR LEU 75 MET SER 78 ASN LEU 75 MET BE 78 THR LEU 75? LE ASN 76 HIS LEU 75 MET ASN 76 HIS
TABLE 10 Triple substitution variants HE 79 LEU VAL 81THRLEU 82 PHE HE 79 LEU VAL 81 THRLEU 82HIS 1LE 79 MET VAL 81 THRLEU 82 PHE ÍLE 79 MET VAL 81 THR LEU 82HIS ILE 79 THR VAL 81 THRLEU 82 PHE HE 79TH VAL 81THRLEU 82 H? S SER 78 ASN VAL 81 THRLEU 82 PHE
SER 78 ASN VAL 81 THRLEU 82 H? S SER 78 THR VAL 81 THRLEU 82 PHE SER 78 THR VAL 81 THRLEU 82HIS SER 78 ASN HE 79 LEU LEU 82 PHE SER 78 ASN HE 79 LEU LEU 82HIS SER 78 ASN HE 79 MET LEU 82 PHE SER 78 ASN ILE 79 MET LEU 82HIS BE 78 ASN HE 79 THR LEU 82 PHE SER 78 ASN ILE 79 THR LEU 82HIS BE 78 THR HE 79 LEU LEU 82 PHE SER 78THRILE 79 LEU LEU 82 HIS
SER 78 THR ILE 79 MET LEU 82 PHE SER 78 THR HE 79 MET LEU 82 H? S SER 78 THR ILE 79 THR LEU 82 PHE SER 78 THR ILE 79 THR LEU 82HIS SER 78 ASN ILE 79 LEU VAL 81THR SER 78 ASN HE 79 MET VAL 81 THR SER 78 ASN HE 79 THR VAL 81 THR SER 78 THR HE 79 LEU VAL 81 THR SER 78 HRHE 79 MET VAL 8THIR BE 78 THR HE 79 TOR VAL 81 THR ASN 76HISVAL 8 THRLEU 82 PHE ASN 76 HiS VAL 8! TOR LEU 82 HiS ASN 76 HJS? LE 79 LEU LEU 82 PHE ASN 76 HIS HE 79 LEU LEU 82 H? S ASN 76 H1S ILE 79 MET LEU 82 PHE ASN 76 HIS ILE 79 MET LEU 82 HIS ASN 76 HIS HE 79 TOR LEU 82 PHE ASN 76 HIS ILE 79 TOR LEU 82 H1S ASN 76 HIS? LE 79 LEU VAL 81 TOR ASN 76 HIS HE 79 MET VAL 81 TOR ASN 76 HIS HE 79 TOR VAL 81 THR ASN 76 H1S SER 78 ASN LEU 82 PHE ASN 76 HiS SER 78 ASN LEU 82 HIS ASN 76 HIS SER 78 TOR LEU 82 PHE ASN 76 HiS SER 78 TOR LEU 82 H1S ASN 76 HIS SER 78 ASN VAL 81 THR ASN 76 H1S SER 78 THR VAL 81 TOR ASN 76 HIS SER 78 ASN HE 79 LEU ASN 76 HIS BE 78 ASN HE 79 MET ASN 76 HIS BE 78 ASN LE 79 TOR ASN 76 H1S SER | THR HE 79 LEU ASN 76 HIS BE 78 TOR HE 79 MET
ASN 76 HIS BE 78 THR LE 79 THR LEU 75 ILE VAL 81 TOR LEU 82 PHE LEU 75 HE VAL 81 THR LEU 82 HIS LEU 75 MET VAL 81 THR LEU 82 PHE LEU 75 MET VAL 81 TOR LEU 82 H1S LEU 75 HE HE 79 LEU LEE 82 LE LE LE 75 75 LE LE LE LE LE 75 75 LE LE 75 LE LE 75 75 LE LE 75 75 LE LE 75 LE LE 75 75 HE LE LE 75 75 HE LE LE 75 75 LE LE 75 75 LE LE 75 75 LE LE 75 82 HIS LEU 75 MET HE 79 LEU LEU 82 PHE LEU 75 MET HE 79 LEU LEU 82 H1S
LEU 75 MET HE 79 MET LEU 82 PHE LEU 75 MET HE 79 MET LEU 82 HIS LEU 75 MET ILE 79 THR LEU 82 PHE LEU 75 MET HE 79 TO LEU 82 H? S LEU 75 HE HE 79 LEU VAL 81 TOR LEU 75 HE HE 79 MET VAL 81 THR LEU 75 ILE 1LE 79 THR VAL 81 THR LEU 75 MET HE 79 LEU VAL 81 TOR LEU 75 MET HE 79 MET VAL 81 THR LEU 75 KffiT ILE 79 TOR VAL 81 TOR LEU 75? LE SER 78 ASN LEU 82 PHE LEU 75 HE BE 78 ASN LEU 82 HIS
LEU 75? LE SER 78 THR LEU 82 PHE LEU 75 HE BE 78 TOR LEU 82 HIS LEU 75 MET BE 78 ASN LEU 82 PHE LEU 75 MET BE 78 ASN LEU 82 H? S LEU 75 MET BE 78 TOR LEU 82 PHE LEU 75 MET BE 78 THR LEU 82 H? S LEU 75? LE SER 78 ASN VAL 81 THR LEU 75 ILE SER 78 TOR VAL 81 TOR LEU 75 MET SER 78 ASN VAL 81 TOR LEU 75 MET SER 78 TUR VAL 81 TOR LEU 75 ILE SER 78 ASN HE 79 LEU LEU 75? LE BE 78 ASN ILE 79 MET LEU 75 ILE BE 78 ASN ILE 79 THR LEU 75 ILE BE 78 THR HE 79 LEU LEU 75 ILE BE 78 THR HE 79 MET LEU 75 ILE BE 78 THR? LE 79 THR LEU 75 MET BE 78 ASN iLE 79 LEU 75 MET BE 78 ASN HE 79 MET LEU 75 MET BE 78 ASN? LE 79 THR LEU 75 MET BE 78 THR ILE 79 LEU LEU 75 MET BE 78 THR HE 79 MET LEU 75 MET BE 78 THR? LE 79 THR LEU 75? LE ASN 76 HIS LEU 82 PHE LEU 75 ILE ASN 76 HIS LEU 82 HIS LEU 75 MET ASN 76 HIS LEU 82 PHE LEU 75 MET ASN 76 HIS LEU 82 HIS LEU 75 ILE ASN 76 HIS VAL 81 THR LEU 75 MET ASN 76 HIS VAL 81 THR LEU 75 HE ASN 76 HISELE 79 LEU LEU 75 HE ASN 76 HIS ILE 79 MET LEU 75 HE ASN 76 HIS HE 79 THR LEU 75 MET ASN 76 HIS HE 79 LEU
LEU 75 MET ASN 76 HIS HE 79 MET LEU 75 MET ASN 76 HIS? LE 79 TOR LEU 75 HE ASN 76 HIS BE 78 ASN LEU 75 HE ASN 76 HIS BE 78 THR LEU 75 MET ASN 76 HIS BE 78 ASN LEU 75 MET ASN 76 H? S SER 78 THR TABLE 11 Quad replacement variants SER 78 ASN HE 79 LEU VAL 81 THR LEU 82 PHE
SER 78 AS ILE 79 LEU VAL 81 THR LEU 82 HIS BE 78 ASN HE 79 MET VAL 81 TOR LEU 82 PHE SER 78 ASN ILE 79 MET VAL 8 i THR LEU 82 HIS SER 78 ASN ILE 79 THR VAL 81 THR LEU 82 PHE SER 78 ASN HE 79 TOR VAL 81 TOR LEU 82 HIS SER 78 THR HE 79 LEU VAL 81 TOR LEU 82 PHE SER 78 THR HE 79 LEU VAL 81 TOR LEU 82 HIS SER 78 THR HE 79 MET VAL 81 TOR LEU 82 PHE SER 78 THR? LE 79 MET VAL 8! THR LEU 82 H1S SER 78 THR ILE 79 THR VAL 81 TOR LEU 82 PHE SER 78 THR ILE 79 TOR VAL 81 THR LEU 82 HIS ASN 76 H? S HE 79 LEU VAL 81 TOR LEU 82 PHE
ASN 76 H? S ILE 79 LEU VAL 81 TH LEU 82 HIS ASN 76 HIS ILE 79 MET VAL 81 TOR LEU 82 PHE ASN 76 HIS ILE 79 MET VAL 81 THR LEU 82 HIS ASN 76 HIS ILE 79 THR VAL 81 THR LEU 82 PHE ASN 76 HISELE 79 THR VAL 81 TOR LEU 82 HIS ASN 76 HIS BE 78 ASN VAL 81 THR LEU 82 PHE ASN 76 H1S SER 78 ASN VAL 81 THR LEU 82 HiS ASN 76 HIS SER 78 TOR VAL 1 THR LEU 82 PHE ASN 76 HIS BE 78 TOR VAL 81 TOR LEU 82 HIS ASK 76 HIS BE 78 ASN HE 79 LEU LEU 82 PHE ASN 76 HIS BE 78 ASN LE 79 LEU LEU 82 HIS ASN 76 HIS BE 78 ASN LE 79 MET LEU 82 PHE ASN ? 6 HIS BE 78 ASN HE 79 MET LEU 82 HiS ASN 76 H? S BE 78 ASN HE 79 TOR LEU 82 PHE ASN 76 HIS BE 78 ASN? LE 79 TOR LEU 82 HIS ASN 76 HIS BE 78 THR ÍLE 79 LEU LEU 82 PHE ASN 76 HIS BE 78 TOR ILE 79 LEU LEU 82 H? S ASN 76 HIS BE 78 TORILE 79 MET LEU 82 PHE ASN 76 HIS BE 78 THR LE 79 MET LEU 82 H? S ASN 76 H1S SER 78 THR ILE 79 THR LEU 82 PHE ASN 76 HIS BE 78 TOR HE 79 THR LEU 82 HIS ASN 76 HIS BE 78 ASN HE 79 LEU VAL 81 THR ASN 76 H¡S SER 78 ASN LE 79 MET VAL 81 TOR ASN 76 H¡S SER 78 ASN HE 79 TOR VAL 81 THR ASN 76 HIS SER 78 THR HE 79 LEU VAL 81 TOR ASN 76 HiS SER 78 THR HE 79 MET VAL 81 TOR ASN 76 HJS SER 78 TOR HE 79 THR VAL 81 THR LEU 75 LE ILE 79 LEU VAL 8! THR LEU 82 PHE LEU 75 JLE HE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 ILE ILE 79 MET VAL 81 TOR LEU 82 PHE LEU 75 LE HE 79 MET VAL 81 THR LEU 82 HIS LEU 75 HE? LE 79 THR VAL 81 TOR LEU 82 PHE
LEU 75 ÍLE ILE 79 THR VAL 81 THR LEU 82 HIS LEU 75 MET HE 79 LEU VAL 81 TOR LEU 82 PHE LEU 75 MET HE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 MET HE 79 MET VAL 81 THR LEU 82 PHE LEU 75 MET HE 79 MET VAL 81 TOR LEU 82 HIS LEU 75 MET? LE 79 TOR VAL 81 THR LEU 82 PHE LEU 75 MET HE 79 THR VAL 81 THR LEU 82 HIS LEU 75 HE BE 78 ASN VAL 81 THR LEU 82 PHE LEU 75 ? LE BE 78 ASN VAL 81 TOR LEU 82 HIS LEU 75 ILE BE 78 THR VAL 81 THR LEU 82 PHE LEU 75 ILE SER 78 THR VAL 81 THR LEU 82 HIS LEU 75 MET BE 78 ASN VAL 81 TOR LEU 82 PHE LEU 75 MÉT SER 78 ASN VAL 8t THR LEU 82 HIS
LEU 75 MET BE 78 THR VAL 81 THR LEU 82 PHE LEU 75 MET BE 78 THR VAL 81 THR LEU 82 HIS LEU 75 HE BE 78 ASN HE 79 LEU LEU 82 PHE LEU 75 ILE BE 78 ASN HE 79 LEU LEU 82 HIS LEU 75 ILE BE 78 ASN ILE 79 MET LEU 82 PHE LEU 75 HE BE 78 ASN HE 79 MET LEU 82 HIS LEU 75 HE BE 78 ASN HE 79 THR LEU 82 PHE LEU 75 ILE BE 78 ASN ILE 79 THR LEU 82 HIS LEU 75 ILE BE 78 TOR HE 79 LEU LEU 82 PHE LEU 75 ILE BE 78 THR 1LE 79 LEU LEU 82 HIS LEU 75 LE BE 78 THR HE 79 MET LEU 82 PHE LEU 75 HE BE 78 THR HE 79 MET LEU 82 HIS
LEU 75 LE BE 78 TOR HE 79 TOR LEU 82 PHE LEU 75 HE BE 78 TOR HE 79 TOR LEU 82 HIS LEU 75 MET BE 78 ASN HE 79 LEU LEU 82 PHE LEU 75 MET BE 78 ASN LE 79 LEU LEU 82 H? S LEU 75 MET BE 78 ASN LE 79 MET LEU 82 PHE LEU 75 MET BE 78 ASN LE 79 MET LEU 82 HIS LEU 75 MET BE 78 ASN HE 79 TOR LEU 82 PHE LEU 75 MET BE 78 ASN ÍLE 79 THR LEU 82 H1S LEU 75 MET BE 78 TOR LE 79 LEU LEU 82 PHE LEU 75 MET BE 78 TOR LE 79 LEU LEU 82 HIS LEU 75 MET BE 78 THR LE 79 MET LEU 82 PHE LEU 75 MET SER 78 TOR 79 MET LEU 82 HIS LEU 75 MET BE 78 THR LE 79 THR LEU 82 PHE LEU 75 MET BE 78 TOR HE 79 THR LEU 82 H¡S LEU 75 HE BE 78 ASN HE 79 LEU VAL 8 i THR LEU 75 LE 78 BE ASN LE 79 MET VAL 81 THR LEU 75 HE BE 78 ASN ÍLE 79 THR VAL 81 THR LEU 75 HE BE 78 THR LE 79 LEU VAL 81 THR LEU 75 HE BE 78 TOR HE 79 MET VAL 81 TOR LEU 75 HE BE 78 THR HE 79 THR VAL 81 TOR LEU 75 MET BE 78 ASN iLE 79 LEU VAL 81 TOR LEU 75 MET BE 78 ASN? LE 79 MET VAL 81 TOR LEU 75 MET BE 78 ASN ILE 79 TOR VAL 81 TOR LEU 75 MET BE 78 TOR HE 79 LEU VAL 81 THR LEU 75 ET SER 78 THR HE 79 MET VAL 81 TOR LEU 75 MET SER 78 TOR ILE 79 TOR VAL 81 TOR LEU 75 LE ASN 76 HIS VAL 81 TOR LEU 82 PHE LEU 75 HE ASN 76 HIS VAL 81 TUR LEU 82 HIS LEU 75 MET ASN 76 HIS VAL 81 TOR LEU 82 PHE LEU 75 MET ASN 76 H1S VAL 81 TOR LEU 82 HIS LEU 75 HE ASN 76 HIS HE 79 LEU LEU 82 PHE LEU 75 LE ASN 76 HIS HE 79 LEU LEU 82 H1S
LEU 75 ÍLE ASN 76 HIS HE 79 MET LEU 82 PHE LEU 75 HE ASN 76 HIS ILE 79 MET LEU 82 HIS LEU 75 HE ASN 7 HIS HE 79 THR LEU 82 PHE LEU 75 HE ASN 76 H? S ILE 79 TOR LEU 82 HIS LEU 75 MET ASN 76 HiS HE 79 LEU LEU 82 PHE LEU 75 MET ASN 76 HIS HE 79 LEU LEU 82 HIS LEU 75 MET ASN 76 HIS ILE 79 MET LEU 82 PHE LEU 75 MET ASN 76 HIS HE 79 MET LEU 82 H? S LEU 75 MET ASN 76 HJS HE 79 TOR LEU 82 PHE LEU 75 MET ASN 76 HIS ILE 79 TOR LEU 82 HIS LEU 75 ÍLE ASN 76 H1S HE 79 LEU VAL 81 THR LEU 75 HE ASN 76 HIS ILE 79 MET VAL 81 TOR
LEU 75 HE ASN 76 HIS HE 79 THR VAL 81 THR LEU 75 MET ASN 76 HIS HE 79 LEU VAL 81 THR LEU 75 MET ASN 76 HIS HE 79 MET VAL 8¡ TOR LEU 75 MET ASN 76 HIS HE 79 TOR VAL 81 THR LEU 75 ILE ASN 76 HIS BE 78 ASN LEU 82 PHE LEU 75? LE ASN 76 HIS BE 78 ASN LEU 82 HIS LEU 75 ILE ASN 76 HIS BE 78 THR LEU 82 PHE LEU 75 LE ASN 76 HIS BE 78 TOR LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 ASN LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 ASN LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 TOR LEU 82 PHE LEU 75 MET ASN 76 HIS BE 78 TOR LEU 82 H? S LEU 75 HE ASN 76 HIS BE 78 ASN VAL 81 TOR
LEU 75 HE ASN 76 HIS SER 78 TOR VAL 8 i TOR LEU 75 MET ASN 76 HIS SER 78 ASN VAL 81 TOR LEU 75 MET ASN 76 HIS SER 78 TOR VAL 81 TOR LEU 75 iLE ASN 76 HIS SER 78 ASN HE 79 LEU LEU 75 ILE ASN 76 HIS BE 78 ASN ILE 79 MET LEU 75 ILE ASN 76 HIS BE 78 ASN HE 79 THR LEU 75 HE ASN 76 HIS BE 78 TOR HE 79 LEU LEU 75 LE ASN 76 HIS BE 78 THR ILE 79 MET LEU 75 HE ASN 76 HJS BE 78 THR? LE 79 THR LEU 75 MET ASN 76 HIS BE 78 ASNILE 79 LEU LEU 75 MET ASN 76HISSER 78 ASN HE 79 MET LEU 75 MET ASN 76 HIS BE 78 ASN HE 79 THR LEU 75 MET ASN 76 H? S SER 78 THR? LE 79 LEU LEU 75 MET ASN 76 HIS SER 78 THR ILE 79 MET LEU 75 MET ASN 76 HIS BE 78 THR ILE 79 THR TABLE 12 Substitute variants five-fold ASN 76 H? S SER 78 ASN HE 79 LEU VAL 8ITHR LEU 82 PHE
ASN 76 HIS BE 78 ASN? LE 79 LEU VAL 81 THR LEU 82 HIS
ASN 76 HIS BE 78 ASN HE 79 MET VAL 81 THR LEU 82 PHE
ASN 76 H1S SER 78 ASN ILE 79 MET VAL 1 THR LEU 82 HIS
ASN 76 H? S SER 78 ASN ILE 79 THR VAL 81 THR LEU 82 PHE
ASN 76 H? S BE 78 ASN HE 79 THR VAL 81 THR LEU 82 H1S
ASN 7 HISSER 78 THR? LE 79 LEU VAL 81 THRLEU 82 PHE
ASN 76 H1S BE 78 THR HE 79 LEU VAL 1 THR LEU 82 HIS
ASN 76 HIS BE 78 THR HE 79 MET VAL 81THRLEU 82 PHE
ASN 76 H1S BE 78 THR HE 79 MET VAL 81 THR LEU 82 HiS
ASN 76HISSER 78 THR HE 79 THR VAL 81 THRLEU 82 PHE
ASN 76 HIS BE 78 THR HE 79 TOR VAL 81 THR LEU 82 HIS
LEU 75 HE BE 78 ASN HE 79 LEU VAL 81 THR LEU 82 PHE
LEU 75 HE BE 78 ASN HE 79 LEU VAL 8 i THR LEU 82 HIS
LEU 75 ILE BE 78 ASN HE 79 MET VAL 81 THR LEU 82 PHE
LEU 75 HE BE 78 ASN HE 79 MET VAL 81 THRLEU 82 HIS
LEU 75 HE BE 78 ASN? LE 79 THR VAL 81 THR LEU 82 PHE
LEU 75 HE BE 78 ASN HE 79 THR VAL 81 THRLEU 82 HIS
LEU 75 HE BE 78 THR HE 79 LEU VAL 81 THR LEU 82 PHE
LEU 75 HE BE 78 THR HE 79 LEU VAL 81 THR LEU 82 HIS
LEU 75 HE BE 78 THR ILE 79 MET VAL 81 THR LEU 82 PHE
LEU 75 HE BE 78THRILE 79 MET VAL S1THRLEU 82H1S
LEU 75 HE BE 78 THR HE 79 THR VAL 81 THR LEU 82 PHE
LEU 75 HE BE 78 THR HE 7 THRVAL 81 THRLEU 82 H? S
LEU 75 MET BE 78 ASN HE 79 LEU VAL 81 TH LEU 82 PHE
LEU 75 MET BE 78 ASN ILE 79 LEU VAL 81 THR LEU 82 H1S
LEU 75 ETSER 78 ASN HE 79 MET VAL 81 THRLEU 82 PHE
LEU 75METSER 78 ASN HE 7 M1TVAL 81 THRLEU 82HIS
LEU 75 ETSER 78 ASN HE 79 THR VAL 81 THRLEU 82 PHE
LEU 75 MET BE 78 ASN HE 79 THR VAL 81 THRLEU 82 H? S
LEU 75 MET BE 78 THR HE 79 LEU VAL $ 1 THRLEU 82 PH!
LEU 75 MET BE 78 THR HE 79 LEU VAL 81 TUR LEU 82 H? S
LEU 75 MET BE 78THRHE 79 MET VAL 81 TUR LEU 82 PHE
LEU 75 MET BE 78 THR HE 79 MET VAL 81 TH LEU 82 HIS
LEU 75 MET SER 7S THR HE 79 THR VAL 81 THR LEU 82 PHE
LEU 75 MET BE 78 THR HE 79 THR VAL 81 THRLEU 82 H? S
LEU 75 HE ASN 76 HIS HE 79 LEU VAL 81 THR LEU 82 PHE
LEU 75 ÍLE ASN 76HISILE 79 LEU VAL 81 THR LEU $ 2 H? S
LEU 75 HE ASN 76 HiS HE 79 ETVAL 8 i THRLEU 82 PHE
LEU 75 ÍLE ASN 7 HISHE 79 MET VAL 81 THRLEU 82 HIS
LEU 75 HE ASN 76H1SHE 79 THR VAL 81THRLEU 82 PHE
LEU 75 HE ASN 76HISHE 79 THR VAL 81 THRLEU 82 HIS
LEU 75 MET ASN 76 HiS? LE 79 LEU VAL 81 TOR LEU 82 PHE
LEU 75 MET ASN 76 HIS HE 79 LEU VAL 81 THR LEU 82 H1S LEU 75 MET ASN 76 H? S HE 79 MET VAL 81 THR LEU 82 PHE
LEU 75 MET ASN 76 HIS HE 79 MET VAL 81 THR LEU 82 HIS
LEU 75 MET ASN 76 HIS HE 79 THR VAL 81 THR LEU 82 PHE
LEU 75 MET ASN 76 HIS HE 79 THR VAL 81 THR LEU 82 HIS
LEU 75 HE ASN 76 H1S SER 78 ASN VAL 81 THR LEU 82 PHE
LEU 75 HE ASN 76 HIS BE 78 ASN VAL 81 THR LEU 82 HIS
LEU 75 HE ASN 76 HIS BE 78 THR VAL 81 THR LEU 82 PHE
LEU 75 ILE ASN 76 HIS BE 78 THR VAL 8¡ THR LEU 82 HiS
LEU 75 MET ASN 76 HIS BE 78 ASN VAL 81 THR LEU 82 PHE
LEU 75 MET ASN 76 HIS BE 78 ASN VAL 81 THR LEU 82 HIS
LEU 75 MET ASN 76 H1S BE 7S H AL 8í THR LEU 82 PHE
LEU 75 MET ASN 76 HIS BE 78 THR VAL 81 TOR LEU 82 H? S
LEU 75 ILE ASN 76 HIS BE 78 ASN? LE 79 LEU LEU 82 PHE LEU 75 HE ASN 76 H? S BE 78 ASNILE 79 LEU LEU 82 H? S
LEU 75 HE ASN 76 HIS BE 78 ASN HE 79 MET LEU 82 PHE
LEU 75 ÍLE ASN 76 HIS BE 78 ASN ILE 79 MET LEU 82 H1S
LEU 75? LE ASN 76 H? S BE 78 ASN HE 79 THR LEU 82 PHE LEU 75 ÍLE ASN 76 H? S SER 78 ASN ÍLE 79 TOR LEU 82 H? S
LEU 75 HE ASN 76 HIS BE 78 THR ILE 79 LEU LEU 82 PHE LEU 75 LE ASN 76 HIS BE 78 THR ILE 79 LEU LEU 82 HIS
LEU 75 ILE ASN 76 HIS BE 78 THR HE 79 MET LEU 82 PHE LEU 75 ILE ASN 76 HIS BE 78 THR ÍLE 79 MET LEU 82 HIS
LEU 75 HE ASN 76 HIS BE 78 THR HE 79 THR LEU 82 PHE LEU 75 HE ASN 76 H? S BE 78 THR ILE 79 TOR LEU 82 HIS
LEU 75 MET ASN 76 HIS BE 78 ASN ÍLE 79 LEU LEU 82 PHE
LEU 75 MET ASN 76 HIS BE 78 ASN HE 79 LEU LEU 82 HIS
LEU 75 MET ASN 76 HIS BE 78 ASN HE 79 MET LEU 82 PHE
LEU 75 MET ASN 76 HIS BE 78 ASN? LE 79 MET LEU 82 HIS
LEU 75 MET ASN 76 HIS BE 78 ASN ÍLE 79 THR LEU 82 PHE
LEU 75 MET ASN 76 HIS SER 78 ASN ILE 79 TOR LEU 82 HIS
LEU 75 MET ASN 76 HIS BE 78 THR ÍLE 79 LEU LEU 82 PHE
LEU 75 MET ASN 76 HIS BE 78 THR HE 79 LEU LEU 82 HiS
LEU 75 MET ASN 76 HIS BE 78 THR ILE 79 MET LEU 82 PHE
LEU 75 MET ASN 76 HIS BE 78 THR HE 79 MET LEU 82 HIS
LEU 75 MET ASN 76 HIS BE 78 THR ILE 79 THR LEU 82 PHE
LEU 75 MET ASN 76 HIS BE 78 THR HE 79 TOR LEU 82 HIS
LEU 75 HE ASN 76 H1S BE 78 ASN HE 79 LEU VAL 81 THR
LEU 75 HE ASN 76 HIS BE 78 ASN? LE 79 MET VAL 8 i THR
LEU 75 HE ASN 76 H? S BE 78 ASN? LE 79 TOR VAL 81 THR
LEU 75 HE ASN 76 HiS SER 78 THR HE 79 LEU VAL 81 THR
LEU 75 HE ASN 76 HIS BE 78 THR ILE 79 MET VAL 81 TOR
LEU 75 HE ASN 76 HIS BE 78 THR HE 79 TOR VAL 81 TOR
LEU 75 MET ASN 76 H? S SER 78 ASN ILE 79 LEU VAL 8 i THR
LEU 75 MET ASN 76 HIS BE 78 ASN HE 79 MET VAL 81 THR
LEU 75 MET ASN 76 HIS BE 78 ASN? LE 79 THR VAL 81 THR
LEU 75 MET ASN 76 H1S SER 78 THR HE 79 LEU VAL 81 THR
LEU 75 MET ASN 76 HIS BE 78 THR HE 79 MET VAL 81 THR
LEU 75 MET ASN 76 HIS BE 78 T? R? LE 79 TOR VAL 81 TOR PICTURE 13 Replacement variants sextuple LEU 75 ILE ASN 76 HIS SER 78 ASN ILE 79 LEU VAL 81 TOR LEU 82 PHE LEU 75 HE ASN 76 HIS BE 78 ASN HE 79 LEU VAL 81 TOR LEU 82 H3S LEU 75 LE ASN 76 HIS BE 78 ASN ILE 79 MET VAL 81 TOR LEU 82 PHE LEU 75 ILE ASN 76 H1S SER 78 ASN HE 79 MET VAL 8! THR LEU 82 H? S LEU 75 ILE ASN 76 HIS BE 78 ASN ILE 79 THR VAL 8 i THR LEU S2 PHE LEU 75 ILE ASN 76 HIS BE 78 ASN? LE 79 THR VAL 8 i THR LEU 82 HIS LEU 75 ILE ASN 76 HiS SER 78 THR? LE 79 LEU VAL 8¡ THR LEU 82 PHE LEU 75 ILE ASN 76 HIS BE 78 THR HE 79 LEU VAL 8? THR LEU 82 H? S LEU 75 ILE ASN 76 HIS BE 78 THR ILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HERE BE 78 THR HE 79 MET VAL 81 THR LEU 82 HIS LEU 75 iLE ASN 76 H1S SER 78 THR HE 79 THR VAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS BE 78 THR 1LE 79 THR VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HIS BE 78 ASN HE 79 LEU VAL 8! THR LEU 82 PHE LEU 75 MET ASN 76 HIS BE 78 ASN HE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HIS BE 78 ASN ILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HIS BE 78 ASN ILE 7 METVAL 8Í THR LEU 82 HIS LEU 75 MET ASN 76 HIS BE 78 ASN HE 79 THR VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HIS BE 78 ASN ILE 79 TOR VAL 81 THR LEU 82 HiS LEU 75 MET ASN 76 H? S BE 78 THR HE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HIS BE 78 THR? LE 79 LEU VAL 81 THR LEU 82 H1S LEU 75 MET ASN 76 HIS BE 78 THR HE 79 MET VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HIS BE 78 THR HE 79 MET VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 H1S BE 78 THR HE 79 THR VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HIS BE 78 THR HE 79 THR VAL 81 THR LEU 82 HIS
One or more additional substitution mutations ("stabilizing substitutions") outside the epitope region can be further made to, for example, re-stabilize the protease during mutation of the epitope region or to increase the proteolytic activity of the variant. Many of these stabilizing mutations are well known in the art. Examples of stabilizing mutations are described, for example, in WO 95/10591, Baeck et al., Published April 20, 1995; patent of E.U.A. No. 4,914,031, Zukowski et al., Issued April 3, 1990; patent of E.U.A. No. 5,470,733, Brvan et al., Issued November 28, 1995; patent of E.U.A. No. 5,567,601, Brvan et al., Issued October 22, 1996; WO 89/07642, patent of E.U.A. No. 5,707,848, Brvan et al., Issued January 13, 1998; Van Eekelen et al., Published on August 24, 1989; WO 87/04461, Stabinskv et al., Published July 30, 1987; patent of E.U.A. No. 4,760,025, Estell et al., Issued July 26, 1988; WO 92/11348, Branner et al., Published July 9, 1992; EP 0,405,901, Casteleün et al., Published January 2, 1991; WO 91/00345, Branner et al., Published January 10, 1991; and WO 94/10020, Brode et al., published March 23, 1995. Preferred stabilizer mutations include one or more of I107V; K213R; Y217L; Y217K; N218S; G169A; M50F; Q19E; P5A; S9A; I31 L; E156S; G169A; N212G; S188P; T254A; S3C + Q206C; and Q271 E. Most preferred stabilizing mutations include one or more of P5A; S9A; 131 L; E156S; G169A; N212G; S188P; T254A; S3C + Q206C; Q271 E; Y217L and Y217K. More preferred stabilizing mutations include Y217 and Y217K. A preferred variant for use in personal care compositions is? 75-83, Y217L.
Manufacturing method Variants are prepared by mutation of the nucleotide sequences encoding the wild-type serine protease, thus resulting in variants having modified amino acid sequences. Such methods are well known in the art; One of these methods is the one explained below:
A phagemid (pSS-5) containing the wild type BNP 'subtilisin gene (Mitchison C. and JA Wells, "Protein Engineering of Disulfide Bonds in Subtilisin BPN", Biochemistry, Vol. 28, pp. 4807-4815 ( 1989) is transformed into CJ236 strain of Escherichia coli dut-ung and a single DNA template containing single chain uracil is produced using the auxiliary phage of VCSM13 (Kunkel et al., "Rapid and Efficient Site-Specific Mutagenesis Without Phenotipic Selection ", Methods in Enzymology, Vol 154, pp. 367-382 (1987), as modified by Yuckenbert et al.," Site-Directer in vitro Mutagenesis Using Uracil-Containing DNA and Phagemid Vectors ", Directed Mutagenesis - A Practical Approach, McPherson, MJ ed., Pp. 27-48 (1991). Site-directed mutagenesis modified from the Zoller and Smith method (Zoller, MJ, and M Smith, Oligonucieot.de-Directed Mutagenesis Using M13-Derived Vectors: An Efficient and General Procedure for the Point Production Mutations in any DNA Fragment ", Nucleic acids Research, Vol. 10, pp. 6487-6500 (1982) is used to produce all mutants (essentially as presented by Yuckenberg et al., Supra). The oligonucleotides are made using a 380B DNA synthesizer (Applied Biosystems Inc.). The mutagenesis reaction products are transformed into the Escherichia coli strain MM294 (American Type Culture Collection E. coli 33625). All mutations are confirmed by DNA sequencing and the isolated DNA is transformed into the expression strain PG632 of Bacillus subtilis (Saunders et al., "Optimization of the Signal-Sequience Cleavage Site for Secretion From Bacillus subtilis of to 34-amino acid. Fragment of Human Parathyroid Homone "; Gene, Vol. 102, pp. 277-282 (1991) and Yang et al.," Cloning of the neutral Protease Gene of Bacillus subtilis and the Use of the Cloned Gene to Créate an in 'íro -Derived Deletion Mutation ", Journal of Bacteriology, Vol. 160, pp. 15-21 (1984). The preliminary evaluation of variant activity is determined by the ability of PG632 cells transformed with mutant plasmids to hydrolyze casein. The fermentation is done as follows. Bacillus subtilis cells (PG632) containing the variant of interest are grown to mid-log phase in one liter of LB broth containing 10 g / L of glucose, and inoculated in a Biotat C fermentor (Braun Biotech, Inc., Allentown, PA) in a total volume of 9 liters. The fermentation medium contains yeast extract, casein hydrosylate, partially hydrolyzed starch, soluble (Maltrin M-250), anti-foam, pH regulators and trace minerals (see "Biology of Bacilli: Aplications to Industry", Doi ,. RH and M. McGloughlin, eds. (1992)). The broth is maintained at a constant pH of 7.5 during the fermentation operation. Kanamycin (50 μg / mL) is added for antibiotic selection of the mutagenized plasmid. The cells are cultured for 18 hours at 37 ° C at an Aβ0 of about 60 and the product is harvested. The fermentation broth is collected through the following steps to obtain a pure variant. Bacillus subtilis cells are removed from the broth by tangential flow against a membrane of 0.16 μm. The cellless broth is then concentrated by ultrafiltration with a molecular weight cut-off membrane of 8000. The pH is adjusted to 5.5 with concentrated MES pH regulator (2- (N-mofoino) ethanesulfonic acid). The variant is then purified by cation exchange chromatography with S-sepharose and eluted with NaCl gradients. (See Scopes, RK, "Protein Purification Principles and Practice," Springer-Verlag, New York (1984) .A pNA test (DelMar et al., Analytical Biochemistry, Vol. 99, pp. 316-320 (1979)) is used to determine the concentration of active variant for fractions collected during gradient elution This test measures the rate at which p-nitroaniline is released as the variant hydrolyzes the soluble synthetic substrate, succinyl-alanine-alanine-proline phenylalanine-p-nitroaniline (sAAPF-pNA) The yellow-colored production rate of the hydrolysis reaction is measured at 410 nm in a spectrophotometer and is proportional to the concentration of active enzyme, In addition, absorbance measurements at 280 nm are used to determine the total protein concentration, the ratio of active enzyme / total protein gives the purity of the variant, and is used to identify fractions that have to be deposited for the supply solution. Utolysis of the variant during storage, weight of propylene glycol is added equal to the deposited fractions obtained from the chromatographic column. Upon completion of the purification procedure, the purity of the supply variant solution is verified with SDS-PAGE (sodium dodecyl sulfate polyacrylamide gel electrophoresis) and the absolute enzyme concentration is determined by a titration method of active site using trypsin inhibitor type II-T: turkey egg white (Sima Chemical Company, St. Louis, Missouri). During preparation for use, the enzyme supply solution is eluted through an explosion-sized Sephadex-G25 column (Pharmaci, Piscataway, New Jersey) to remove the propylene glycol and exchange the pH regulator. The MES pH regulator in the enzyme supply solution is exchanged for the 0.1 M tris pH buffer (tris (hydroxymethyl aminomethane) containing 0.01 M CaCl2 and the pH is adjusted to 8.6 with HCl. carried out with a pH of 8.6 in a tris pH regulator with a thermostat at 25 ° C.
Analytical Methods The variants of the present invention can be tested for enzymatic activity and immune and / or allergenic response using the following methods, which are known to those skilled in the art. Alternatively, other methods well known in the art can be used.
Activity of a variant The protease activity of a variant of the present invention can be tested by methods that are well known in the art. Such methods are discussed below:
Skin flake activity method Through the use of Scotch® # 3750G tape, flakes of human skin are separated from the legs of a subject repeatedly until the tape is substantially opaque with flakes. The tape is then cut into squares of 2.54 by 2.54cm. and it is left aside. In a 10mm petri dish. by 35mm., 2mL of 0.75 mg / mL of a control enzyme (for example, subtilisin BPN ') or the variant to be tested is added the pH regulator of KH2PO4 0.01 M at a pH of 5.5. To this solution is added 1 mL of 2.5% sodium laurate at a pH of 8.6. The solution is mixed gently on a platform shaker. The box of previously prepared tape is soaked in the solution (the leaflet was up) for ten minutes continuing the smooth mixing. The tape box is then gently rinsed in tap water for fifteen seconds. Stevenel blue dye pipette (3 ml, commercially available from Sigma Chemical Co., St. Louis, MO) was applied in a clean petri dish. The rinsed tape box is placed in the dye for 3 minutes (with the leaflet facing up) with gentle mixing. The tape box is removed from the dye and rinsed consecutively in two 300 ml beakers with distilled water, for 15 seconds by rinsing. The tape box is allowed to air dry. The color intensity between the tape frame obtained from the control enzyme and the tape box obtained from the variant is visually compared or using a chromameter. In relation to the control enzyme tape frame, a table 3
Variant tape that shows less color intensity indicates a variant that has higher activity.
Collagen-dyed activity method 50 ml of 0.1 M tris pH-regulator (tris-hydroxymethylaminomethane) containing 0.01 M CaCl2 are combined to give a pH of 86, and 0.5 grams of azocol (collagen impregnated with azo dye, commercially available from Sigma Chemical Co., St. Louis, MO). This mixture is incubated at 25 ° C while mixing gently with a platform shaker. 2 ml of the mixture is filtered through a 0.2 micron syringe cylinder and the absorbance of the mixture is read at 520 nm to zero a spectrophotometer. One ppm of a control enzyme (eg, subtilisin BPN ') of the variant to be tested is added to the remaining 48 ml of tris / azocol mixture. 2 ml of the control / variant containing solution is filtered through a syringe filter of 2 microns every two minutes for a total of ten minutes. For each filtered sample, the absorbance is read immediately at 520 nm. The results are plotted against time. The slopes of the control and the test conjugate indicate relative activities of the samples. A higher slope indicates a higher activity. The test variant activity (pending) can be expressed as percent of the control activity (pending).
T Cell Proliferation Test The immune and / or allergenic potential of variants of the variants of the present invention can be determined using a T cell proliferation test such as the test presented below. This test is a variation of the test described in Bunqy Poor Fard et al., "T Cell Epitopes of the Major Fraction of Rye Grass Lolium Perennial (Lol p I) Defined Using Overlapping Peptides in vitro and in vivo", Clinical Experimental Immunology, Vol. 94, pp. 111-116 (1993). The blood of subjects allergic to subtilisin BPN '(positive to prick test) and control subjects (negative to prick test) are used in this test. The blood (~ 60 ml) of each of the subjects is collected and the mononuclear cells are harvested using ficoll-hypaque (obtainable from Pharmacia, Piscataway, New Jersey). The cells are washed twice in RPMI 1640 (obtainable from Gibco, Grand Island, New York) and then resuspended in complete RPMI medium supplemented with 10% 10% human AB serum, 2 mM L-glutamine. and 25 μg / mL of gentamicin (available from Gibco). The cells are cultured at a concentration of 2 x 10 5 cells / well in 0.2 ml of complete medium in 96-well microtitre plates with U-bottom. The potential antigen to be tested (either BPN 'inactivated as control positive or a variant of the present invention is added to a final concentration of up to 40 μg / ml Cultures are incubated at 37 ° C in 5% CO 2 After 5 days, 1 μCi / methyl-3H-thymidine cavity The cells are harvested and later harvested.The incorporation of 3H-thymidine by the cells is evaluated as a measurement of T cell proliferation by liquid scintillation counting.
Compositions of the present invention The variants of the present invention can be used in any application that is suitable for the respective wild-type protease. An example of this type includes cleaning compositions. Due to the desirable allergenicity and / or reduced immunogenicity properties of the variants of the present invention, the variants can be further used in applications that benefit from a minimum of the use of proteases. Examples of such applications include those in which the variant is necessarily in close contact with human skin, such as with the use of personal care compositions.
Cleaning compositions The variants may be used in cleaning compositions including, but not limited to laundry compositions, hard surface cleaning compositions, light duty cleaning compositions including tableware cleaning compositions and automatic dishwashing detergent compositions.
The cleaning compositions of the present invention comprise an effective amount of one or more variants of the present invention and a vehicle of cleaning composition. As used herein, "effective amount of variants", or the like, refers to the necessary amount of variant to achieve the necessary proteolytic activity in the specific cleaning composition. Said effective amounts are easily investigated by one of ordinary skill in the art and are based on many factors, such as the particular variant used, the cleaning application, the specific composition of the cleaning composition and whether a liquid or dry composition is desired (e.g. , granulated, in bar), and the like. Preferably, the cleaning compositions are comprised of from about 0.0001% to about 10%, most preferably from about 0.001% to about 1% and, most preferably, from about 0.01% to about 0.1% of one or more variants of this invention . Several examples of different cleaning compositions in which the variants can be used are discussed in more detail below. In addition to these variants, these cleaning compositions further consist of a vehicle of the cleaning composition containing one or more materials of the cleaning composition compatible with the variant. The term 'cleaning composition material', as used herein, means any material selected for the particular type of cleaning composition desired and the shape of the product (eg, liquid, granulate, stick, aerosol, pellet). , in paste, in gel), whose materials are also compatible with the variant used in the composition. The specific selection of materials of the cleaning composition is carried out with ease considering the material to be cleaned and the desired form of the composition for cleaning conditions during use. The term 'compatible', as used herein, means that the materials of the cleaning composition do not reduce the proteolytic activity of the variant to such a degree that the variant is not as effective as desired during situations of normal use. The specific materials of the cleaning composition are exemplified in detail below. The variants of this invention can be used in a variety of detergent compositions in which it is desired to obtain a high degree of foaming and a good cleaning activity. Therefore, the variants can be used with several common ingredients in order to provide hard surface cleaners of complete formulation, dishwashing compositions, fabric washing compositions, and the like. Said compositions may be in liquid, granulated, bar and the like form. Such compositions can be formulated as 'concentrated' detergents containing from about 30% to about 60% by weight of surfactants. The cleaning compositions herein may optionally contain, and preferably, various surfactants (for example, anionic, nonionic or zwitterionic surfactants). Such surfactants are typically present at levels of about 5% to about 35% of the compositions. Non-limiting examples of the surfactants useful herein include the C 8 -C 8 alkylbenzenesulfonates and the common primary and random alkyl sulfates, the secondary C 2 -C 7 alkylsulphates of the formulas CH 3 (CH 2) α ( CHOS03) "M +) CH3 and CH3 (CH2) and (CHOSO3" M +) CH2CH3, where x and (y + 1) are integers of at least about 7, preferably at least about 9, and M is a cation soluble in water, especially sodium; C10-C18 alkylalkoxy sulfates (especially EO 1-5 ethoxysulfates), C10-C18 alkylalkoxycarboxylates (especially EO 1-5 ethoxycarboxylates), alkyl polyglycosides of C-io-C-is and their corresponding sulfated polyglucosides, esters of C12-C18 α-sulphonated fatty acids, C12-C? alkyl and alkylphenolalkoxylates (especially ethoxylates and ethoxy / mixed propoxy), betaines and sulfobetaines ('sultaines') of C ?2-C? s, amine oxides C-to-C-is, and the like. Preferred herein are alkylalkoxy sulfates (AES) and alkylalkoxycarboxylates (AEC). The use of such surfactants in combination with the amine oxide and / or betaine or sultaine surfactants is also preferred, depending on what the formulator desires. Other common useful surfactants are mentioned in normal texts. Particularly useful surfactants include the N-methyl glucamides of C-io-C-iß described in U.S. Patent No. 5,194,639, Connor et al., Issued March 16, 1993.
A wide variety of other ingredients useful in detergent cleaning compositions can be included in the compositions herein, including, for example, other active ingredients, carriers, hydrotropes, processing aids, dyes or pigments, and solvents for liquid formulations. If it is desired to obtain an additional foaming increase, they can be incorporated in the foam-enhancing compositions, such as C10-Ci6 alkolamides, typically at levels of about 1% to about 10%. Cio-C monoethanolamides and diethanolamides illustrate a typical class of such foam enhancers. It is also convenient to use said foam boosters with auxiliary foaming surfactants, such as the amine oxides, betaines and sultaines mentioned above. If desired, soluble magnesium salts, such as MgCl 2, MgSO and the like, can be added, typically at levels of from about 0.1% to about 2% to provide additional foaming. The liquid detergent compositions herein may contain water and other solvents as carriers. The primary or secondary low molecular weight alcohols are exemplary, exemplified by methanol, ethanol, propanol and / or so-propanol. Monohydric alcohols are preferred for solubilizing surfactants, but polyols, such as those containing from about 2 to about 6 carbon atoms and from about 2 to about 6 hydroxy groups (eg, 1,3-propanediol, ethylene glycol), can also be used. , glycerin and 1,2-propanediol). The compositions may contain from about 5% to about 90%, typically from about 10% to about 50%, of said vehicles. The detergent compositions herein will be formulated, preferably, such that during use in aqueous cleaning operations, the wash water contains a pH between about 6.8 and about 11. The finished products are generally formulated on this scale. Techniques for controlling pH at recommended levels of use include the use of, for example, pH, alkali and acid regulators. Such techniques are well known to those skilled in the art. In formulating the hard surface cleaning compositions and fabric cleaning compositions of this invention, the formulator may wish to employ various builders at levels of from about 5% to about 50% by weight. Typical builders include zeolites of 1 to 10 microns, polycarboxylates, such as citrates and oxydisuccinates, extralated silicates, phosphates and the like. Other common detergency builders are mentioned in the normal forms. Also, the formulator may wish to employ several additional enzymes, such as cellulases, lipases, amylases and proteases in said compositions, typically at levels from about 0.001% to about 1% by weight. Various detersive and fabric care enzymes are well known in the laundry detergent art.
Various bleaching compounds, such as percarbonates, perborates and the like, can be used in such compositions, typically at levels of about 1% to about 15% by weight. If desired, said compositions may contain bleach activators, such as tetraacetylethylenediamine, nonanoyloxybenzenesulfonate and the like, which are also known in the art. Usage levels vary, generally, from about 1% to about 10% by weight. Dirt releasing agents, especially of the anionic oligoester type; chelating agents, especially aminophosphonates and ethylenediamine disuccinates; clay soil removal agents, especially ethoxylated tetraethylenepentamine; dispersing agents, especially polyacrylates and polyaspartates; polishes, especially anionic polishes, suds suppressors, especially silicones and secondary alcohols; Fabric softeners, especially smectite clays, and the like, can be used in said compositions at levels ranging from about 1% to about 35% by weight. Normal forms and published patents contain multiple detailed descriptions of such common materials. Also, enzyme stabilizers can be used in the cleaning compositions. Said enzyme stabilizers include propylene glycol (preferably from about 1% to about 10%), sodium formate (preferably from about 0.1% to about 1%) and calcium formate (preferably from about 0.1% to about 1%) . The variants of the present invention are useful in hard surface cleaning compositions. The expression 'hard surface cleaning compositions', as used herein, refers to liquid and granular detergent compositions for cleaning hard surfaces, floors, walls, bathroom tiles and the like. The hard surface cleaning compositions of this invention comprise an effective amount of one or more variants of this invention, preferably from about 0.001% to about 10%, most preferably from about 0.01% to about 5%, still more preferably about 0.05% to about 1% by weight variant composition. In addition to consisting of one or more variants, said hard surface cleaning compositions are generally constituted by surfactants and water-soluble sequestering builders. However, in certain specialized products, such as aerosol glass cleaners, the surfactants are sometimes not used, since they can produce a residue in the form of a layer and / or streaking on the surface of the glass. The surfactant component, when present, may comprise at least 0.1% of the compositions herein, but, generally, the compositions will contain from about 0.25% to about 10%, preferably from about 1% to about 5%. % surfactant. Commonly, the compositions will contain from about 0.5% to about 50% of a builder, preferably from about 1% to about 10%. Preferably, the pH should fall within the range of about 7 to about 12. Common pH adjusting agents, such as sodium hydroxide, sodium carbonate or hydrochloric acid, may be employed if an adjustment is required. Solvents may be included in the compositions. Useful solvents include, but are not limited to, glycol ethers, such as diethylene glycol monohexyl ether, diethylene glycol monobutyl ether, ethylene glycol monobutyl ether, ethylene glycol monohexyl ether, propylene glycol monobutyl ether, dipropylene glycol monobutyl ether, and diols, such as ethylene glycol. , 2,4-trimethyl-1,3-pentanediol and 2-ethyl-1,3-hexanediol. When used, said solvents are present, generally, at levels of from about 0.5% to about 15%, preferably from about 3% to about 11%. Also, highly volatile solvents, such as / so-propanol or ethanol, can be used in these compositions to facilitate that the composition evaporates faster from surfaces when the surface is not cleaned after a 'full concentration' application of the composition to the surface. When used, volatile solvents are usually present at levels of about 2% to about 12% in the compositions. The hard surface cleaning compositions of this invention are illustrated by the following examples.
EXAMPLES 1-6 Liquid compositions for hard surface cleaning
All formulas are adjusted to a pH of 7. In Examples 1-6, the variants cited in Tables 2-10, and the preferred variants cited herein, inter alia, replace G70 * + S78 * + I79 * , with substantially similar results. In another embodiment of this invention, dishwashing compositions consist of one or more variants of this invention. The term 'dishwashing composition', as used herein, refers to all forms of dishwashing compositions, including the forms
granulated and liquid, but not limited to them. The dishwashing compositions of this invention are illustrated by the following examples.
EXAMPLES 7-10 Liquid dishwashing detergent
All the formulas are adjusted to a pH of 7. In Examples 7-10, the variants cited in Tables 2-10, and preferred variants cited herein, among others, replace G70 * + L75 * + N76 * + N77 * + S78 * + I79 * + G80 * + V81 * + L82 *, with substantially similar results. The liquid fabric cleaning compositions of this invention are illustrated by the following examples.
EXAMPLES 11-13 Liquid compositions for fabric cleaning
In Examples 11-13, the variants cited in Tables 2-10, and preferred variants cited herein, inter alia, replace G70 *, with substantially similar results.
Compositions for personal care
These variants are especially suitable for use in personal care compositions, such as non-rinsing and rinse-on hair conditioners, shampoos, non-rinse and rinse-off anti-acne compositions, facial milks and conditioners, shower-bath gels, soaps, facial cleansers and foaming cleansers. no skimmers, cosmetics, lotions and body, facial and hand moisturizers, non-rinsing facial moisturizers, cosmetic wipes and cleansers, oral care compositions and contact lens care compositions. These personal care compositions comprise one or more variants of this invention and a personal care vehicle. By way of illustration, these variants are suitable for inclusion in the compositions described in the following references: U.S. Patent No. 5,641, 479, Linares et al., Issued June 24, 1997 (cleansers for the skin); U.S. Patent No. 5,599,549 Wivell et al., Issued February 4, 1997 (cleansers for the skin); U.S. Patent No. 5,585,104, Ha et al., Issued December 17, 1996 (cleansers for the skin); U.S. Patent No. 5,540,852, Kefauver et al., Issued July 30, 1996 (cleansers for the skin); U.S. Patent No. 5,510,050, Dunbar et al., Issued April 23, 1996 (cleansers for the skin); U.S. Patent No. 5,612,324, Guanq Lin et al., Issued March 18, 1997 (anti-acne preparations); U.S. Patent No. 5,587,176, Warren et al., Issued December 24, 1996 (anti-acne preparations); U.S. Patent No. 5,549,888, Venkateswaran, issued on August 27, 1996 (anti-acne preparations); U.S. Patent No. 5,470,884, Corless et al., Issued November 28, 1995 (anti-acne preparations); U.S. Patent No. 5,650,384, Gordon et al., Issued July 22, 1997 (gels for shower bath); U.S. Patent No. 5,607,678, Moore et al., Issued March 4, 1997 (gels for shower bath); U.S. Patent No. 5,624,666, Coffindaffer et al., Issued April 29, 1997 (conditioners and / or hair shampoos); U.S. Patent No. 5,618,524, Bolich et al., Issued April 8, 1997 (conditioners and hair shampoos); U.S. Patent No. 5,612,301, Inman, issued March 18, 1997 (conditioners and hair shampoos); U.S. Patent No. 5, 573,709, Wells, issued November 12, 1996 (conditioners and / or hair shampoos); U.S. Patent No. 5,482,703, Pinqs, issued January 9, 1996 (conditioners and / or hair shampoos); U.S. Patent No. Re. 34, 584, Grote et al. Grate et al., Reissued on April 12, 1994 (conditioners and / or hair shampoos); U.S. Patent No. 5,641, 493, Date et al., Issued June 24, 1997 (cosmetics); U.S. Patent No. 5,605,894, Blank et al., Issued February 25, 1997 (cosmetics); U.S. Patent No. 5,585,090, Yoshioka et al., Issued December 17, 1996 (cosmetics); U.S. Patent No. 4,939,179, Cheney et al., Issued July 3, 1990 (lotions for hands, face and / or body); U.S. Patent No. 5,607,980, McAtee et al., Issued March 4, 1997 (lotions for hands, face and / or body); U.S. Patent No. 4,045,364, Richter et al., Issued August 30, 1997 (cosmetic cloths and cleansers); European patent application EP 0619074, Touchet et al., published on October 12, 1994 (cosmetic cloths and cleansers); U.S. Patent No. 4,475,217, Brown-Skrobot et al., Issued December 4, 1990 (cosmetic cloths and cleansers); U.S. Patent No. 5,096,700, Seibel, issued March 17, 1992 (compositions for oral cleaning); U.S. Patent No. 5,028,414, Sampathkumar, issued July 2, 1991 (compositions for oral cleaning); U.S. Patent No. 5,028,415, Benedict et al., Issued July 2, 1991 (compositions for oral cleaning); U.S. Patent No. 5,028,415, Benedict et al., Issued July 2, 1991 (compositions for oral cleaning); U.S. Patent No. 4,863,627, Davies et al., September 5, 1989 (cleaning solutions for contact lenses); U.S. Patent No. Re. 32,672, Huth et al., Reissued on May 24, 1988 (cleaning solutions for contact lenses); and U.S. Patent No. 4,609,493, Schafer, issued September 2, 1986 (cleaning solutions for contact lenses). To further illustrate the oral cleansing compositions of this invention, an amount of one or more pharmaceutically acceptable variants of this invention is included in compositions useful for removing proteinaceous stains from teeth or dentures. The term 'compositions oral cleansing', as used herein, refers to dentifrices, toothpastes, tooth gels, tooth powders, mouthwashes, mouth sprays, mouth gels, chewing gums, tablets, pouches, tablets, biogels, prophylactic pastes, dental treatment solutions and the like. Preferably, the oral cleaning compositions consist of from about 0.0001% to about 20% of one or more variants of this invention, most preferably from about 0.001% to about 10%, most preferably still from about 0.01% to about 5% in composition weight, and a pharmaceutically acceptable vehicle. The term "pharmaceutically acceptable", as used herein, means that the drugs, medicaments or inert ingredients described by the term are suitable for use in contact with human and lower animal tissues without risking undue toxicity, incompatibility. , instability, irritation, allergic response and the like, in proportion to a reasonable benefit / risk ratio. Typically, the pharmaceutically acceptable components of the buccal cleaning vehicle of the buccal cleaning components of the buccal cleaning compositions will generally be comprised of from about 50% to about 99.99%, preferably from about 65% to about 99.99%, most preferably from about 65% to about 99%, by weight of the composition. The pharmaceutically acceptable components of the vehicle and the optional components that can be included in the buccal cleaning compositions of this invention are well known to those skilled in the art. A wide variety of types of compositions, vehicle components and optional components useful in oral cleaning compositions is described in the references cited above. In another embodiment of this invention, denture cleansing compositions for cleaning dentures outside the buccal cavity comprise one or more variants of this invention. Said denture cleansing compositions consist of an effective amount of one or more variants, preferably from about 0.0001% to 0
about 50% of one or more variants, most preferably from about 0.001% to about 35%, even more preferably from about 0.01% to about 20%, by weight of the composition, and a denture cleansing vehicle. Various formats of denture cleansing compositions, such as effervescent tablets and the like, are well known in the art (see, for example, U.S. Patent No. 5,055,305, Young) and, in general, are suitable for incorporating one or more variants for Remove proteinaceous spots from dentures. In another embodiment of this invention, contact lens cleaning compositions consist of one or more variants of this invention. Said contact lens cleaning compositions contain an effective amount of one or more variants, preferably from about 0.01% to about 50% of one or more variants, most preferably from about 0.01% to about 20%, even more preferably from about 1% to about 5%, by weight of the composition, and a contact lens cleaner vehicle. Various formats of contact lens cleaning compositions, such as tablets, liquids and the like, are well known in the art and are generally suitable for incorporating one or more variants of this invention to remove proteinaceous stains from contact lenses. The contact lens cleaning composition embodiment of this invention is illustrated by examples 14-17.
EXAMPLES 14-17 Contact lens cleaning solution
In Examples 14-17, the variants cited in Tables 2-10, and the preferred variants cited herein, among others, replace N76 *, with substantially similar results. Examples 18-21 illustrate the use of these variants in products for washing the body:
EXAMPLES 18-21 Products for washing the body
In Examples 18-21, the variants cited in Tables 2-10, and preferred variants cited herein, inter alia, replace L75 * + N76 * + N77 * + S78 * + I79 * + G80 * + V81 * + L82 *, with substantially similar results. Examples 18-21 illustrate the use of these variants in facial cleansers:
EXAMPLES 22 TO 25 Products for washing the face
In Examples 22-25, the variants cited in Tables 2-10, and preferred variants cited herein, inter alia, replace L75 *, with substantially similar results.
Examples 26-27 illustrate the use of these variants in non-rinsing skin moisturizing compositions:
EXAMPLES 26-27 Non-rinsing composition skin moisturizer
In Examples 26-27, the variants cited in Tables 2-10, and preferred variants cited herein, among others, replace L82 *, with substantially similar results. Example 28 illustrates the use of these variants in compositions applied to cleaning cloths.
EXAMPLE 28 Composition in cleaning cloths
The above composition is impregnated in an absorbent woven cloth composed of cellulose and / or polyester at about 250% by weight of the absorbent cloth. In Example 28, the variants cited in Tables 2-10, and preferred variants cited herein, among others, replace S78 *, with substantially similar results.
LIST OF SEQUENCES
(1. GENERAL INFORMATION:
(i) APPLICANT: RUBINGH, D.N. et al.
(I) TITLE OF THE INVENTION: SERINE PROTEASE VARIANTS THAT HAVE DECREASED IMMUNOGENICITY
(iii) NUMBER OF SEQUENCES: 1
(iv) ADDRESS OF CORRESPONDENCE: (A) RECIPIENT: THE PROCTER & GAMBLE COMPANY
(B) STREET: 11810 EAST MIAMI RIVER ROAD (C) CITY: ROSS (D) STATE: OH (E) COUNTRY: E.U.A. (F) POSTAL CODE: 45061
(v) COMPUTER LEADABLE FORM: (A): TYPE OF MEDIUM: Flexible disk (B) COMPUTER: IBM compatible PC (C) OPERATING SYSTEM: PC-DOS / MS-DOS (D) SOFTWARE: Patentln Relay # 1.0, Version # 1.30
(vi) CURRENT DATA OF THE APPLICATION: (A) APPLICATION NUMBER: (B) DATE OF SUBMISSION: (C) CLASSIFICATION:
(viii) INFORMATION OF THE APPORTER / AGENT: (A) NAME: HERSKO, BART S. (B) REGISTRATION NUMBER: 32,572 (C) CASE NUMBER:
(ix) TELECOMMUNICATIONS INFORMATION: (A) TELEPHONE: 513-627-0633 (B) TELEFAX: 513-627-0260
(2) INFORMATION FOR SEQ ID NO: 1:
(i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 275 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) DESCRIPTION OF SEQUENCE: SEQ ID NO: 1:
Ala Gln Ser Val Pro Tyr Gly Val Ser Gln lie Lys Ala Pro Ala Leu 1 5 10 15
His Ser Gln Gly Tyr Thr Gly Ser Asn Val Lys Val Wing Val lie Asp 20 25 30 Ser Gly lie Asp Being Ser His Pro Asp Leu Lys Val Wing Gly Gly Wing 35 40 45 Ser Met Val Pro Ser Glu Thr Asn Pro Phe Gln Asp Asn Asn Ser His 50 55 60 Gly Thr His Val Ala Gly Thr Val Ala Ala Leu A = n Asn Ser lie Gly 65 70 75 80
Val Leu Gly Val Ala Pro Ser Ala Ser Leu Tyr Ala Val Lys Val Leu 85 90 95
Gly Wing Asp Gly Ser Gly Gln Tyr Ser Trp He He Asn Gly He Glu 100 105 110 Trp Wing Wing Asn Asn Met Asp Val lie Asn Met Ser Leu Gly Gly 115 120 125 Pro Ser Gly Ser Ala Ala Leu Ala Ala Ala Val Asp Lys Wing Val Wing 130 135 140 Ser Gly Val Val Val Val Wing Wing Wing Gly Asn Glu Gly Thr Ser Gly 145 150 155 160
Being Ser Thr Val Gly Tyr Pro Gly Lys Tyr Pro Ser Val He Wing 165 170 175
Val Gly Ala Val Asp Ser As Asn Gln Arg Ala Ser Phe Ser Ser Val 180 185 190 Gly Pro Glu Leu Asp Val Met Wing Pro Gly Val Ser He Gln Ser Thr
195 200 205 Leu Pro Gly Asn Lys Tyr Gly Wing Tyr Asn Gly Thr Ser Met Wing Being
210 215 220 Pro His Val Ala Gly Ala Ala Ala Ala Leu He Leu Ser Lys His Pro Asn
225 230 235 240
Trp Thr A = n Thr Gln Val Arg Ser Ser Leu Glu Asn Thr Thr Thr Lys 245 250 255
Leu Gly Asp Ser Phe Tyr Tyr Gly Lys Gly Leu He Asn Val Gln Wing 260 265 270 Wing Wing Gln 275
Claims (10)
1. A variant of serine protease characterized by a modified amino acid sequence of a wild-type amino acid sequence consisting of a substitution by an amino acid substituent at a position corresponding to positions 70-84 of subtilisin BPN ', wherein: a) When the substitution occurs at position 70, the amino acid substituent is cted from the group consisting of Ala, Arg, Asn, Asp, Cys, Glu, Phe, His, Lie, Lys, Leu, Met, Pro, Gln, Ser, Thr , Trp, Tyr and Val; b) When the substitution occurs at position 71, the amino acid substituent is cted from the group consisting of Ala, Arg, Asn, Cys, Gly, Phe, His, Lie, Lys, Leu, Met, Pro, Gln, Ser, Trp , Tyr and Val; c) When the substitution occurs at position 72, the amino acid substituent is cted from the group consisting of Ala, Arg, Asn, Asp, Cys, Glu, Gly, Phe, His, Lie, Lys, Leu, Met, Pro, Gln , Ser, Thr, Trp, Tyr and Val; d) When the substitution occurs at position 73, the amino acid substituent is cted from the group consisting of Arg, Asn, Asp, Cys, Glu, Gly, Phe, His, Lie, Lys, Met, Pro, Ser, Thr, Trp , Tyr and Val; e) When the substitution occurs at position 74, the amino acid substituent is cted from the group consisting of Arg, Asn, Asp, Cys, Glu, Gly, Phe, His, Lie, Lys, Leu, Met, Gln, Ser, Thr , Trp, Tyr and Val; f) When the substitution occurs at position 75, the amino acid substituent is cted from the group consisting of Ala, Arg, Asn, Asp, Cys, Glu, Gly, Phe, His, Lie, Lys, Met, Gln, Ser, Thr , Trp, Tyr and Val; g) When the substitution occurs at position 76, the substituent amino acid is cted from the group consisting of Ala, Arg, Cys, Lie, Leu, Met, Gln, Ser, Thr, Trp, Tyr and Val; h) When the substitution occurs at position 77, the amino acid substituent is cted from the group consisting of Ala, Arg, Cys, Glu, Gly, Phe, His, Lie, Lys, Leu, Met, Pro, Gln, Ser, Thr , Trp, Tyr and Val; i) When the substitution occurs at position 78, the amino acid substituent is cted from the group consisting of Ala, Arg, Asn, Cys, Glu, Gly, Phe, His, Lie, Lys, Leu, Met, Pro, Gln, Thr , Trp, Tyr and Val; j) When the substitution occurs at position 79, the amino acid substituent is cted from the group consisting of Ala, Arg, Asn, Cys, Gly, Phe, His, Lys, Leu, Met, Pro, Gln, Ser, Thr, Trp , Tyr and Val; k) When the substitution occurs at position 80, the amino acid substituent is cted from the group consisting of Ala, Arg, Asn, Asp, Cys, Glu, Phe, His, Lie, Lys, Leu, Met, Pro, Gln, Ser , Thr, Trp, Tyr and Val; I) When the substitution occurs at position 81, the amino acid substituent is cted from the group consisting of Ala, Arg, Asn, Asp, Cys, Glu, Gly, Phe, His, Lie, Lys, Leu, Met, Pro, Gln , Ser, Thr, Trp and Tyr; m) When the substitution occurs at position 82, the amino acid substituent is cted from the group consisting of Ala, Arg, Asn, Asp, Cys, Glu, Gly, Phe, His, He, Lys, Met, Pro, Gln, Ser , Thr, Trp, Tyr and Val; n) When the substitution occurs at position 83, the amino acid substituent is cted from the group consisting of Ala, Arg, Asn, Asp, Cys, Glu, Phe, His, Lie, Lys, Leu, Met, Pro, Gln, Ser , Thr, Trp, Tyr and Val; i) When the substitution occurs at position 84, the amino acid substituent is cted from the group consisting of Ala, Arg, Asn, Asp, Cys, Glu, Gly, Phe, His, lie, Lys, Leu, Met, Pro, Gln , Ser, Thr, Trp and Tyr. 2. A variant of serine protease further characterized by a modified amino acid sequence of a wild-type amino acid sequence consisting of a substitution by an amino acid substituent at two or more positions corresponding to positions 71-84 of subtilisin of BPN ' , wherein: a) When a substitution occurs at position 70, the amino acid substituent is cted from the group consisting of Ala, Arg, Asn, Asp, Cys, Gln, Glu, Phe, His, He, Lys, Leu, Met , Pro, Ser, Thr, Trp, Tyr and Val; b) When a substitution occurs at position 71, the amino acid substituent is selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, Phe, His, lie, Lys, Leu, Met, Pro , Ser, Trp, Tyr and Val; c) When a substitution occurs at position 72, the amino acid substituent is selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, Phe, His, lie, Lys, Leu, Met, Pro , Ser, Thr, Trp and Tyr; d) When a substitution occurs at position 73, the amino acid substituent is selected from the group consisting of Arg, Asn, Asp, Cys, Gln, Glu, Gly, Phe, His, He, Lys, Leu, Met, Pro, Ser , Thr, Trp, Tyr and Val; e) When a substitution occurs at position 74, the amino acid substituent is selected from the group consisting of Arg, Asn, Asp, Cys, Gln, Glu, Gly, Phe, His, He, Lys, Leu, Met, Pro, Ser , Thr, Trp, Tyr and Val; f) When a substitution occurs at position 75, the amino acid substituent is selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, Phe, His, lie, Lys, Met, Pro, Ser , Thr, Trp, Tyr and Val; g) When a substitution occurs at position 76, the amino acid substituent is selected from the group consisting of Ala, Arg, Asp, Cys, Gln, Glu, Gly, Phe, His, lie, Lys, Leu, Met, Pro, Ser , Thr, Trp, Tyr and Val; h) When a substitution occurs at position 77, the amino acid substituent is selected from the group consisting of Ala, Arg, Asp, Cys, Gln, Glu, Gly, Phe, His, He, Lys, Leu, Met, Pro, Ser , Thr, Trp, Tyr and Val; i) When a substitution occurs at position 78, the amino acid substituent is selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, Phe, His, He, Lys, Leu, Met, Pro , Thr, Trp, Tyr and Val; j) When a substitution occurs at position 79, the amino acid substituent is selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, Phe, His, Lys, Leu, Met, Pro, Ser , Thr, Trp, Tyr and Val; k) When a substitution occurs at position 80, the amino acid substituent is selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Gln, Glu, Phe, His, Me, Lys, Leu, Met, Pro, Ser , Thr, Trp, Tyr and Val; I) When a substitution occurs at position 81, the amino acid substituent is selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Gln.Glu, Gly, Phe, His, He, Lys, Leu, Met, Pro , Ser, Thr, Trp and Tyr; m) When a substitution occurs at position 82, the amino acid substituent is selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, Phe, His, lie, Lys, Met, Pro, Ser , Thr, Trp, Tyr and Val; n) When a substitution occurs at position 83, the amino acid substituent is selected from the group consisting of Ala, Arg, Asn, Asp, Cys, GIn, Glu, Phe, His, lie, Lys, Leu, Met, Pro, Ser , Thr, Trp, Tyr and Val; and o) When a substitution occurs at position 84, the substituent amino acid is selected from the group consisting of Ala, Arg,
Asn, Asp, Cys, Gln, Glu, Gly, Phe, His, Me, Lys, Leu, Met, Pro, Ser, Thr, Trp and
Tyr. 3. A variant according to claim 1 or 2, further characterized in that the serine protease was selected from the group consisting of subtilisin BPN ', subtilisin Carlsberg, subtilisin DY, subtilisin 309, K proteinase and termitase.
4. A variant according to any of the preceding claims, further characterized in that the substitution is one or more positions 73-83 corresponding to subtilisin BPN '.
5. A variant according to any of the preceding claims, further characterized in that the substitution is one or more positions 70 and 75-82 corresponding to subtilisin BPN '.
6. A variant according to any of the preceding claims, further characterized by one or more stabilizing mutations.
7. A variant according to claim 6, further characterized in that the stabilizing mutations were selected from the group consisting of I107V, K213R, Y217L, Y217K, N218S, G169A, M50F, Q19E, P5A, S9A, I31L, E156S, G169A, N212G, S188P, T254A, S3C + Q206C, and Q271E.
8. - A personal care composition that is constituted by a variant according to any of the preceding claims and a personal care vehicle.
9. A cleaning composition consisting of a variant according to any of the preceding claims and a vehicle of the cleaning composition.
10. A mutant serine protease gene encoding a variant according to any of the preceding claims.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60/079,397 | 1998-03-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA00009434A true MXPA00009434A (en) | 2001-07-09 |
Family
ID=
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6569663B1 (en) | Serine protease variants having amino acid substitutions | |
| US6495136B1 (en) | Proteases having modified amino acid sequences conjugated to addition moieties | |
| US6586223B1 (en) | Subtilisin protease variants having amino acid substitutions in defined epitope regions | |
| US6586224B1 (en) | Subtilisin protease variants having amino acid deletions and substitutions in defined epitope regions | |
| AU750336B2 (en) | Serine protease variants having amino acid deletions and substitutions | |
| JP2004500007A (en) | Stabilizing mutant of subtilisin inhibitor of Streptomyces | |
| US6908757B1 (en) | Serine protease variants having amino acid deletions and substitutions | |
| MXPA00009434A (en) | Serine protease variants having amino acid substitutions | |
| MXPA00009442A (en) | Serine protease variants having amino acid deletions and substitutions | |
| CZ20003397A3 (en) | Serine protease variant, preparation for personal hygiene, cleansing agent mutation gene | |
| AU5928200A (en) | Intramolecularly cross-linked subtilisin proteases having reduced immunogenicity | |
| MXPA00009385A (en) | Protease conjugates | |
| CZ20003394A3 (en) | Serine protease variant, gene mutant and preparation for personal hygiene |