JP7002345B2 - サブチリシン変異体を含む組成物及び方法 - Google Patents
サブチリシン変異体を含む組成物及び方法 Download PDFInfo
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- JP7002345B2 JP7002345B2 JP2018005572A JP2018005572A JP7002345B2 JP 7002345 B2 JP7002345 B2 JP 7002345B2 JP 2018005572 A JP2018005572 A JP 2018005572A JP 2018005572 A JP2018005572 A JP 2018005572A JP 7002345 B2 JP7002345 B2 JP 7002345B2
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- amino acid
- subtilisin
- variant
- acid sequence
- protease
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- 0 CC(C)(*)C(C1C[C@](C2)C2N)*1Cl Chemical compound CC(C)(*)C(C1C[C@](C2)C2N)*1Cl 0.000 description 1
- FLAKYYULMQMQCJ-AVGNSLFASA-N CC(C)C[C@@H](C=O)NC([C@H](C)NC([C@H](C(C)C)NC(OC)=O)=O)=O Chemical compound CC(C)C[C@@H](C=O)NC([C@H](C)NC([C@H](C(C)C)NC(OC)=O)=O)=O FLAKYYULMQMQCJ-AVGNSLFASA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/52—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from bacteria or Archaea
- C12N9/54—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from bacteria or Archaea bacteria being Bacillus
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- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
- C11D3/16—Organic compounds
- C11D3/38—Products with no well-defined composition, e.g. natural products
- C11D3/386—Preparations containing enzymes, e.g. protease or amylase
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- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
- C11D3/16—Organic compounds
- C11D3/38—Products with no well-defined composition, e.g. natural products
- C11D3/386—Preparations containing enzymes, e.g. protease or amylase
- C11D3/38681—Chemically modified or immobilised enzymes
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/21—Serine endopeptidases (3.4.21)
- C12Y304/21062—Subtilisin (3.4.21.62)
Description
本出願は、米国仮出願特許番号第61/332,151号(2010年5月6日出願);同第61/332,006号(2010年5月6日出願);同第61/392,364号(2010年10月12日出願)並びに同第61/392,188号(2010年10月12日出願)の利益を主張する。これらのすべての特許は参照によりその全体が本明細書に組み込まれる。
本発明は、セリンプロテアーゼ変異体を提供する。具体的には、本発明は、参照セリンプロテアーゼと比較した場合に1箇所以上の置換を有するセリンプロテアーゼ変異体を提供する。加えて、本発明は、これらのセリンプロテアーゼ変異体を含む組成物を提供する。一部の実施形態では、本発明は、これらのセリンプロテアーゼ変異体のうちの少なくとも1種を含むクリーニング組成物を提供する。
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-X076D-X101A-X183D-X198L-X249R、X043D-X045T-X101G-X103A-X104I-X232V-X245R-X269R、X018R-X020R-X024R-X076D-X101A-X183D-X198L-X211Q-X249R、X018R-X020R-X043R-X101G-X103A-X104I-X217E-X232V-X245R、X024R-X043R-X076D-X078R-X101G-X103A-X104I-X232V-X245R-X269R、X043R-X045T-X076D-X078R-X101G-X103A-X104I-X166F-X176P-X179V-X184T-X187P-X194P、X018R-X022W-X024R-X041E-X076D-X101A-X160T-X183D-X211Q-X213A-X249R、X018R-X020R-X022W-X024R-X076D-X116A-X183D-X198L-X211Q-X215F-X249R、X018R-X020R-X022W-X024R-X076D-X101A-X116A-X198L-X213A-X249R、X018R-X022W-X024R-X076D-X101A-X116A-X183D-X198L-X211Q-X213A-X249R、X018R-X020R-X024R-X076D-X198L-X213A-X249R、X018R-X020R-X022W-X024R-X076D-X116A-X183D-X198L-X211Q-X249R、X018R-X020R-X024R-X076D-X183D-X211Q-X215F-X249R、X024R-X076D-X104I、X018R-X076D-X101G-X232V、X018R-X024R-X076D-X101A-X116A-X183D-X198L-X211Q-X213A-X215F-X249R、X018R-X020R-X022W-X024R-X076D-X116A-X183D-X215F-X249R、X018R-X024R-X031F-X076D-X116A-X183D-X211Q-X213A-X215F-X249R、X018R-X024R-X076D-X101A-X116A-X183D-X198L-X213A-X249R-X269S、X018R-X020R-X024R-X076D-X101A-X116A-X198L-X215F-X249R、X018R-X043R-X076D-X078R-X101G-X103A-X104I-X232V-X245R-X269R、X018R-X020R-X024R-X076D-X101A-X114T-X198L-X211Q-X215F-X249R、X024R-X043R-X078R-X101G-X103A-X104I-X217E-X232V-X245R、X024R-X076D-X103A-X104I-X232V、X018R-X020R-X022W-X024R-X076D-X101A-X198L-X211Q-X215F-X249R、X101G-X104I-X232V、X018R-X022W-X024R-X076D-X183D-X198L-X213A-X215F-X249R、X018R-X022W-X024R-X076D-X183D-X198L-X211Q-X249R、X018R-X020R-X024R-X076D-X183D-X213A-X249R、X018R-X024R-X076D-X101A-X183D-X211Q-X215F-X249R、X018R-X020R-X022W-X024R-X076D-X116A-X211Q-X213A-X249R、X018R-X078R-X101G-X103A-X104I-X232V-X245R-X269R、X018R-X022W-X024R-X076D-X101A-X116A-X183D-X211Q-X215F-X249R-X260A、X076D-X249R、X018R-X022W-X024R-X076D-X183D-X211Q-X215F-X249R、X018R-X020R-X024R-X076D-X116A-X211Q-X215F-X249R、X018R-X020R-X024R-X076D-X213A-X249R、X018R-X020R-X022W-X024R-X076D-X116A-X183D-X198L-X249R、X018R-X020R-X022W-X024R-X076D-X101A-X183D-X249R、X076D-X104I-X249R、X020R-X022W-X101A-X103A-X104I-X116A-X183D-X211Q-X213A-X215F-X232V-X245R、X024R-X043R-X045T-X078R-X101G-X103A-X104I-X217E-X232V-X245R、X018R-X020R-X022W-X024R-X076D-X183D-X198L-X215F-X249R、X018R-X076D-X101G-X103A、X020R-X024R-X101G-X103A-X104I-X232V-X245R-X269R、X018R-X020R-X024R-X076D-X101A-X116A-X183D-X211Q-X249R、X101G-X103A-X232V、X024R-X076D-X101G-X232V、X018R-X022W-X024R-X076D-X101A-X183D-X198L-X211Q-X249R、X018R-X020R-X024R-X076D-X101A-X183D-X198L-X211Q-X215F-X249R、X018R-X020R-X024R-X076D-X183D-X198L-X249R、X018R-X022W-X024R-X076D-X101A-X116A-X183D-X198L-X211Q-X249R、X018R-X020R-X024R-X076D-X116A-X156V-X183D-X211Q-X215F-X249R-X269S、X045T-X076D-X101G-X103A-X104I-X232V-X245R-X249R、X018R-X020R-X024R-X076D-X101A-X183D-X198L-X249R、X018R-X020R-X022W-X024R-X076D-X198L-X211Q-X215F-X249R、X018R-X020R-X022W-X024R-X076D-X101A-X116A-X198L-X211Q-X215F-X249R、X018R-X020R-X022W-X024R-X076D-X116A-X249R、X018R-X076D-X101G、X018R-X024R-X076D-X116A-X183D-X198L-X213A-X215F-X249R、X018R-X020R-X022W-X024R-X076D-X101A-X116A-X198L-X213A-X215F-X249R、X018R-X024R-X076D-X101A-X116A-X183D-X198L-X211Q-X249R、X018R-X076D-X232V、X018R-X020R-X024R-X076D-X101A-X232V-X245R、X018R-X043D-X045T-X076D-X101G-X103A-X104I-X232V-X245R、X018R-X022W-X024R-X076D-X183D-X213A-X215F-X249R、X018R-X024R-X076D-X101A-X116A-X211Q-X213A-X237D-X249R、X018R-X020R-X024R-X076D-X101A-X116A-X183D-X211Q-X249R-X275S、X018R-X022W-X024R-X076D-X101A-X116A-X183D-X198L-X211Q-X213A-X215F-X249R、X024R-X076D、X018R-X024R-X076D-X183D-X211Q-X215F-X249R、X018R-X022W-X024R-X076D-X116A-X183D-X198L-X213A-X215F-X249R、X076D-X104I-X232V-X249R、X018R-X076D-X103A-X232V、X018R-X020R-X024R-X076D-X101A-X116A-X183D-X198L-X211Q-X213A-X249R、X018R-X020R-X024R-X076D-X101A-X183D-X213A-X249R、X018R-X020R-X024R-X076D-X101A-X175E-X183D-X211Q-X215F-X249R、X018R-X020R-X043D-X078R-X101G-X103A-X104I-X217E-X232V-X245R-X273E、X020R-X024R-X043D-X045T-X076D-X101G-X103A-X104I-X232V-X245R、X005S-X101G-X103A-X104I-X232V-X245R-X249R、X103A-X104I-X232V、X018R-X020R-X024R-X068A-X076D-X101A-X116A-X213A-X215F-X249R、X018R-X022W-X024R-X076D-X101A-X198L-X215F-X249R-X275S、X018R-X024R-X076D-X183D-X198L-X211Q-X213A-X249R、及びX043D-X045T-X101G-X103A-X104I-X232V-X245Rから選択されるアミノ酸置換の組み合わせを含むアミノ酸配列からなり、このサブチリシン変異体のアミノ酸位置は、配列番号1で示されるB.アミロリケファシエンスのサブチリシンBPN’のアミノ酸配列と対応させて番号付けされる、サブチリシン変異体を提供する。
a)以下の変異:X1R、X2S、V4R、V4S、X9A、X10S、X14K、X16S、X22A、X22R、X24R、X25V、X26F、X42I、X52F、X52E、X52N、X62E、X62Q、X68A、X68C、X71G、X72C、X74C、X75A、X75F、X78R、X89P、X89T、X89G、X89H、X89W、X91N、X94N、X100S、X101A、X101N、X101G、X101D、X103G、X103N、X104L、X104I、X108I、X111V、X112V、X115K、X117F、X121F、X128D、X128F、X128L、X128N、X129E、X148I、X158E、X159E、X160D、X166D、X185E、X186H、X188E、X188D、X203E、X209S、X209N、X209F、X209T、X209E、X209H、X209G、X210R、X212I、X212F、X214F、X215N、X215D、X215E、X217E、X217N、X224A、X230E、X231I、X236F、X238R、X238K、X239K、X239G、X239R、X248V、X249R、X250I、X262D、X263F、X265F、X267V、X267N、X269I、X269R、X271F、X271I、X271H及びX272Fのうちの2つ以上を含み、並びに/又は
b)以下の変異の組:X062E-X129E、X062E-X159E、X016S-X148I、X158E-X249R、X016S-X062E、X111V-X188D、X022A-X062E、X062E-X148I、X022A-X129E、X062E-X271F、X062E-X158E、X016S-X159E、X062E-X186H、X128N-X159E、X062E-X188D、X062E-X128N、X148I-X159E、X103G-X158E、X111V-X159E、X158E-X271F、X016S-X188D、X022A-X111V、X128N-X158E、X016S-X158E、X104L-X158E、X128N-X186H、X159E-X209E、X062E-X101A、X111V-X209E、X148I-X188D、X101A-X209E、X022A-X188D、X016S-X022A、X128N-X129E、X016S-X209E、X016S-X128N、X022A-X089P、X128N-X209E、X089P-X158E、X062E-X103G、X186H-X271F、X016S-X129E、X089P-X159E、X111V-X249R、X101A-X129E、X148I-X209E、X022A-X159E、X129E-X249R、X129E-X209E、X104L-X129E、X128N-X188D、X111V-X158E、X022A-X158E、X062E-X209E、X062E-X249R、X101A-X186H、X089P-X129E、X129E-X271F、X22A-X111V-X159E、X101A-X103G-X104L-X209E、X101A-X103G-X104L-X159E、X101A-X103G-X104L-X188D、X101G-X103A-X104I-X159D、X22A-X103G-X159E、X22A-X128N-X271F-X209E、X22A-X209E-X271F、X22A-X101A-X209E、X101A-X209E-X271F、X22A-X111V-X128N、X22A-X101A-X159E、X101A-X103G-X104L、X22A-X101A-X103G-X104L、X101A-X103G-X104L、X101G-X103A-X104I、X101A-X103G-X104L-X128N、X103A-X104I-X159D-X232V-X236H-X245R-X248D-X252K、X101G-X104I-X159D-X232V-X236H-X245R-X248D-X252K、X101G-X103A-X159D-X232V-X236H-X245R-X248D-X252K、X101G-X103A-X104L-X232V-X236H-X245R-X248D-X252K、X101G-X103A-X104L-X159D-X236H-X245R-X248D-X252K、X101G-X103A-X104L-X159D-X232V-X245R-X248D-X252K、X101G-X103A-X104L-X159D-X232V-X236H-X248D-X252K、X101G-X103A-X104L-X159D-X232V-X236H-X245R-X252K、X101G-X103A-X104L-X159D-X232V-X236H-X245R-X248D、X62E-X101G-X103A-X104I-X159D-X232V-X245R-X248D-X271F、X62E-X101G-X103A-X104I-X159D-X232V-X245R-X248D-X249R、X22A-X101G-X103A-X104I-X159D-X232V-X245R-X248D-X249R、X101G-X103A-X104I-X159D-X232V-X245R-X248D-X24R、X101G-X103A-X104I-X159D-X232V-X245R-X248D-X253R、X101G-X103A-X104I-X158E-X232V-X245R-X248D-X249R、X22A-X101G-X103A-X104I-X159D-X232V-X245R-X248D-X271F、X101G-X103A-X104I-X159E-X232V-X245R-X248D-X249R、X101G-X103A-X104I-X159D-X232V-X245R-X248D-X238R、X101G-X103A-X104I-X158E-X232V-X245R-X248D-X271F、X101G-X103A-X104I-X159D-X232V-X245R-X248D、X101G-X103A-X104I-X159D-X232V-X245R-X248D-X271F、X101G-X103A-X104I-X159D-X232V-X245R-X248D-X76D及びX101G-X103A-X104I-X159E-X232V-X245R-X248D-X271Fのうちの1つ以上を含み、上記変異体は、配列番号1のアミノ酸配列を有するB.レンタスのサブチリシンGG36プロテアーゼと比較して0、-1、-2、-3、-4又は-5の正味電荷、好ましくは0、-1、-2又は-3の正味電荷を有する。これらのプロテアーゼ変異体は、イオン強度の低い、又は洗剤濃度の低い水性洗浄液に特に好ましいものであり得る。
a)以下の変異:X4R、X17R、X18R、X20R、X22R、X24R、X24W、X25R、X43R、X43A、X46R、X52F、X52N、X57R、X59A、X62Q、X71G、X75R、X76D、X78R、X82R、X86W、X89P、X89W、X89T、X89I、X89H、X89V、X104L、X106V、X106G、X115R、X118I、X121F、X144R、X185I、X197F、X209N、X209S、X217E、X231I、X239R、X239S、X241R、X242R、X242L、X243R、X244R、X248I、X249R、X252R、X253R、X271T、X271V、X271L、X271H、X271F、X271P、X1R、X9A、X212F及びX269Rのうちの2つ以上を含み、並びに/又は
b)以下の変異の組:X022R-X024R、X009A-X271L、X018R-X241R、X018R-X115R、X043R-X249R、X020R-X249R、X004R-X249R、X020R-X024R、X018R-X249R、X009A-X020R、X020R-X241R、X009A-X078R、X020R-X115R、X018R-X024R、X024R-X242R、X022R-X115R、X018R-X043R、X020R-X043R、X018R-X242R、X242R-X269R、X018R-X244R、X024R-X269R、X020R-X271L、X024R-X271L、X004R-X009A、X020R-X269R、X001R-X024R、X244R-X271L、X009A-X018R、X241R-X271L、X004R-X024R、X009A-X249R、X009A-X022R、X101G-X103A-X104I-X159D-X232V-X245R-X248D-X271F、X101G-X103A-X104I-X158E-X232V-X245R-X248D-X271F、X101G-X103A-X104I-X158E-X232V-X245R-X248D-X249R、X101G-X103A-X104I-X159D-X232V-X245R-X248D-X24R、X101G-X103A-X104L-X159D-X232V-X236H-X245R-X252K、X101G-X103A-X104L-X232V-X236H-X245R-X248D-X252Kのうちの1つ以上を含み、上記プロテアーゼ変異体は、配列番号1のアミノ酸配列を有するB.レンタスのサブチリシンGG36プロテアーゼと比較して0、+1、+2、+3、+4又は+5の合計正味電荷を有し、好ましくは正の合計正味電荷を有し、最も好ましくは+1、+2又は+3の正味電荷を有する。これらのプロテアーゼ変異体は、イオン強度の高い、又は洗剤濃度の高い水性洗浄液に特に好ましいものであり得る。
49R、S101G-S103A-V104I-P129E-G159E-A232V-N238R-Q245R-N248D、S101G-S103A-V104I-A158E-G159E-S188D-A232V-N238R-Q245R-N248D、S024R-S101G-S103A-V104I-A232V-Q245R-N248D-H249R、T022A-S024R-S101G-S103A-V104I-P129E-L148I-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-A158E-A232V-N238R-Q245R-N248D、S101G-S103A-V104I-S128N-P129E-A232V-N238R-Q245R-N248D、T022A-S101G-S103A-V104I-S128N-G159E-A232V-Q245R-N248D、T022A-S101G-S103A-V104I-S128N-P129E-A158E-A232V-N238R-Q245R-N248D、S101G-S103A-V104I-S128N-P129E-S188D-A232V-Q245R-N248D-H249R、T022A-S024R-S101G-S103A-V104I-S128N-P129E-A158E-S188D-A232V-Q245R-N248D-H249R、S024R-S101G-S103A-V104I-S128N-A158E-G159E-S188D-A232V-Q245R-N248D、T022A-S024K-S101G-S103A-V104I-S128N-A158E-G159E-A232V-Q245R-N248D、S101G-S103A-V104I-P129E-L148I-S188D-A232V-Q245R-N248D、S024R-S101G-S103A-V104I-L148I-A232V-Q245R-N248D、T022A-S101G-S103A-V104I-L148I-S188D-A232V-Q245R-N248D、S024R-S101G-S103A-V104I-S128N-P129E-S188D-A232V-Q245R-N248D、S101G-S103A-V104I-S128N-P129E-A158E-A232V-N238R-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-P129E-L148I-A158E-S188D-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-L148I-A158E-S188D-A232V-Q245R-N248D、S101G-S103A-V104I-L148I-G159E-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-A158E-S188D-A232V-Q245R-N248D、及びS101G-S103A-V104I-S128N-P129E-A158E-A232V-Q245R-N248D-H249Rから選択されるアミノ酸置換の組み合わせを含むアミノ酸配列からなり、このサブチリシン変異体のアミノ酸位置は、配列番号1で示されるB.アミロリケファシエンスのサブチリシンBPN’のアミノ酸配列と対応させて番号付けされる、サブチリシン変異体を提供する。
45R、G020R-S101G-I198L-A215F-A232V-Q245R、N018R-S024R-N076D-T213A-A215F-H249R、G020R-S078R-S101G-S103A-V104I-N116A-G211Q-A232V-Q245R、G020R-T022W-S078R-S101A-S103A-V104I-N116A-N183D-A215F-A232V-Q245R、G020R-T022W-S078R-S101A-S103A-V104I-N116A-N183D-T213A-A232V-Q245R、S024R-A232V-Q245R、N018R-S024R-N043D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-S024R-N076D-S101A-A215F-H249R、N018R-T022W-S024R-N076D-N116A-T213A-H249R、S101G-S103A-V104I-A232V-Q245R、N018R-S024R-N076D-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-N116A-T213A-A215F-H249R、N043D-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N043D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、G020R-T022W-S078R-S101G-S103A-V104I-N116A-N183D-G211Q-A232V-Q245R、N018R-S024R-N076D-S101A-I198L-G211Q-A215V-H249R、N018R-T022W-S024R-N076D-N116A-G211Q-H249R、G020R-S103A-V104I-A232V-Q245R、G020R-T22W-S101A-S103A-V104I-G211Q-A215F-A232V-Q245R、S024R-N076D-S101G-S103A-V104I-A232V-Q245R、G020R-S101G-S103A-V104I-N116A-A232V-Q245R、N018R-T22W-S024R-N076D-I198L-A215F-H249R、G020R-T022W-S103A-V104I-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-G211Q-T213A-A232V-Q245R、G020R-T022W-S101G-S103A-V104I-G211Q-T213A-A215F-A232V-Q245R、N018R-N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-S101A-I198L-T213A-A215F-H249R、N018R-T22W-S024R-N076D-S101A-A215F-H249R、G020R-R045T-S101G-S103A-V104I-A232V-Q245R、G020R-S078R-S101G-S103A-V104I-T180A-A232V-Q245R、G020R-T022W-S078R-S101G-S103A-V104I-N116A-N183D-A215F-A232V-Q245R、N018R-S101G-S103A-V104I、G020R-T22W-S101A-S103A-V104I-N116A-G211Q-T213A-A215F-A232V-Q245R、N018R-S024R-N076D-S103A-A232V-Q245R、G020R-S078R-S101A-S103A-V104I-N116A-N183D-A232V-Q245R、N018R-S024R-N076D-G211Q-H249R、G020R-S101A-S103A-V104I-T213A-A215F-A232V-Q245R、N018R-G020R-N043D-S101G-S103A-V104I-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-G211Q-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-N116A-G211Q-A215F-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-N116A-G211Q-A232V-Q245R、N018R-S024R-N076D-A232V-H249R、N018R-S024R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-N076D-Q245R、S024R-V104I-Q245R、S101G-A232V、G020R-T22W-S101A-S103A-V104I-N116A-G211Q-A215F-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-I198L-T213A-H249R、G020R-T022W-S078R-S101A-S103A-V104I-A232V-Q245R、G020R-T022W-S078R-S101A-S103A-V104I-I198L-A232V-Q245R、S024R-Q245R-H249R、G020R-S101G-S103A-V104I-N116A-G211Q-A232V-Q245R、N018R-T22W-S024R-N076D-N116A-G211Q-H249R、S024R-S101G-V104I-H249R、N018R-S024R-N076D-N116A-I198L-G211Q-T213A-A215F-H249R、N018R-S024R-V104I、G020R-T022W-S078R-S101A-S103A-V104I-N183D-I198L-T213A-A215F-A232V-Q245R、N018R-G020R-T22W-S024R-N076D-N116A-N183D-I198L-T213A-H249R、G020R-T022W-S101A-S103A-V104I-A232V-Q245R、Q012H-G020R-S078R-S101G-S103A-V104I-I198L-G211Q-T213A-A232V-Q245R、N018R-S024R-N076D-S101A-G211Q-A215F-H249R、N018R-S024R-N076D-T213A-H249R、S024R-V104I-H249R、N018R-T022W-S024R-N076D-G211Q-H249R、N018R-N076D-S103A-V104I-H249R、N043R-N076D-S101G-S103A-V104I-L217E-A232V-Q245R、G020R-S078R-S101G-S103A-V104I-N183D-G211Q-T213A-A232V-Q245R-E271G、N018R-T022W-S024R-N076D-S101A-N116A-I198L-A215F-H249R、N018R-S024R-N043D-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-S024R-N076D-S101A-I198L-A215F-H249R、N018R-T022W-S024R-N076D-N116A-I198L-G211Q-T213A-H249R、N018R-S024R-N076D-S101A-N116A-T213A-A215F-H249R、G020R-N043D-R045T-S078R-S101G-S103A-V104I-A232V-Q245R、R045T-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-T22W-S024R-N076D-S101A-N116A-A215F-H249R、N043D-S101G-S103A-V104I-A232V-Q245R-N269R、G020R-T022W-S078R-S101A-S103A-V104I-N116A-N183D-T213A-A215F-A232V-Q245R、N018R-S024R-N076D-N116A-G211Q-T213A-A215F-H249R、S024R-S103A-M175L-A232V-H249R、N018R-S024R-N076D-N116A-T213A-H249R、G020R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、G020R-S078R-S101A-S103A-V104I-N116A-N183D-G211Q-T213A-A215F-A232V-Q245R、S024R-N043R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-S024R-N076D-S101A-N116A-I198L-T213A-A215F-H249R、N043R-R045T-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-S101A-I198L-G211Q-Q245R、G020R-S024R-N043D-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、S024R-A232V、G020R-S078R-S101A-S103A-V104I-N116A-N183D-G211Q-A232V-Q245R、S024R-N076D-S101G-A232V-Q245R、N018R-N076D-S101G-S103A-V104I-H249R、N018R-S024R-N076D-I198M-G211Q-T213A-A215F-H249R、N018R-T22W-S024R-N076D-S101A-I198L-A215F-H249R、N018R-N043R-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、G020R-T022W-S103A-G211Q-T213A-A215F-A232V-Q245R、G020R-S078R-S101A-S103A-V104I-N116A-N183D-G211Q-T213A-A232V-Q245R、R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-T22W-S024R-N076D-S101A-G211Q-T213A-H249R、N018R-S024R-N076D-N116A-I198L-A215F-H249R-V268G、N018R-T022W-S024R-N076D-S101A-G211Q-H249R、N018R-T022W-S024R-N076D-S101A-N116A-I198L-G211Q-H249R、S101G-S103A-V104I-Q245R、N018R-N076D-S101G-A232V-Q245R、N018R-G020R-R045T-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-S101A-N116A-I198L-H249R、N018R-T022W-S024R-N076D-N116A-I198L-T213A-H249R、S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、G020R-N043R-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-N043D-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、R045T-S101G-S103A-V104I-A232V-Q245R-N269R、S024R-S103A-A232V、N018R-S024R-N076D-S10
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-H249R、N018R-T022W-S024R-N076D-S101A-N116A-G211Q-T213A-H249R、N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-N076D-S101G-V104I-H249R、N018R-T022W-S024R-N076D-S101A-T213A-A215F-H249R、N018R-T22W-S024R-N076D-S101A-N116A-I198L-A215F-H249R、N018R-G020R-S101G-S103A-V104I-A232V-Q245R-H249R、S101G-S103A-V104I-A232V-Q245R-H249R-N269R、S024R-N076D-Q245R、N018R-G020R-N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-S024R-N076D-A215F-H249R、N018R-S024R-N076D-S101A-N116A-N183D-I198L-T213A-H249R、N018R-G020R-S024R-N076D-G211Q-A215F-H249R、N043D-S101G-S103A-V104I-A232V-Q245R、G020R-T22W-S078R-S101A-S103A-V104I-N116A-N183D-A215F-A232V-Q245R、N018R-S024R-N076D-I198L-G211Q-A215F-H249R、N043R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N043R-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、G020R-N043D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-T022W-S024R-N076D-S101A-T213A-H249R、G020R-T022W-S101A-N116A-I198L-G211Q-T213A-A215F-H249R、N043R-R045T-S078R-S101G-S103A-V104I-N218S-A232V-Q245R、N018R-S103A、G020R-T22W-S101G-S103A-V104I-N116A-N183D-A215F-A232V-Q245R、N018R-S024R-N076D-S101A-H249R、N018R-T022W-S024R-N076D-G211Q-T213A-H249R、S024R-N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-A232V-Q245R、G020R-S101A-S103A-V104I-N116A-N183D-G211Q-T213A-A215F-A232V-Q245R、K027R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、G020R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-G020R-S024R-N076D-N116A-N183D-T213A-A215F-H249R、N018R-S024R-N076D-V104I、S101G-S103A-V104I-A232V-H249R、N018R-S024R-N076D-N116A-N183D-G211Q-H249R、N018R-G020R-S024R-N076D-N116A-A215F-H249R、N018R-S024R-N076D-N183D-T213A-A215F-H249R、N018R-T022W-S024R-N076D-I198L-G211Q-H249R、N043D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R-R275S、G020R-T022W-S101A-S103A-V104I-N116A-N183D-G211Q-A232V-Q245R、N018R-T022W-S024R-N076D-S101A-I198L-G211Q-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-I198L-G211Q-T213A-A215F-H249R、N018R-G020R-S024R-N076D-N183D-H249R、N018R-S024R-N076D-N116A-I198L-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N116A-G211Q-H249R、V004M-N018R-S024R-N076D-N116A-I198L-G211Q-T213A-H249R、V104I-A232V-H249R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-G211Q-A215F-A232V-Q245R、G020R-S101A-S103A-V104I-N116A-N183D-G211Q-A232V-Q245R-T274I、G020R-S101A-S103A-V104I-T213A-A232V-Q245R、G020R-S101G-S103A-V104I-N116A-N183D-G211Q-T213A-A232V-Q245R、G020R-S024R-N043D-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-S024R-N076D-S103A-H249R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-G211Q-A215F-H249R、N018R-G020R-S024R-N076D-N116A-N183D-I198L-H249R、N018R-T022W-S024R-N076D-N116A-I198L-A215F-H249R、N018R-S024R-N076D-S101A-G211Q-T213A-A215F-H249R-A270V、N018R-N043D-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、G020R-T022W-S101G-S103A-V104I-N183D-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-T213A-H249R、N018R-T022W-S024R-N076D-I198L-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-I198L-T213A-H249R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-A232V-Q245R、N018R-T22W-S024R-N076D-N116A-I198L-T213A-H249R、N043R-R045T-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-S024R-N076D-S101G-S103A-V104I-A232V、S101G-H249R、S024R-N076D-S101G-S103A-V104I-M175L-H249R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-A232V-Q245R-N269S、N018R-S024R-N076D-S101A-N116A-I198L-H249R、N018R-T022W-S024R-N076D-N116A-H249R、N018R-G020R-S024R-N076D-S101A-N183D-I198L-A215F-H249R、N018R-S024R-N076D-T213A-A215F-H249R-T260K、N018R-S024R-N076D-N116A-G211Q-T213A-H249R、N018R-G020R-T022W-S024R-N076D-N116A-I198L-H249R、S024R-N076D-S101G-S103A-V104I-Q245R、S024R-N076D-S103A-H249R、N018R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-S024R-N076D-I198L-G211Q-H249R、N018R-T022W-S024R-N076D-S101A-I198L-G211Q-T213A-H249R、G020R-S024R-R045T-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-S024R-N076D-N183D-G211Q-T213A-H249R、N018R-N043D-R045T-S078R-S101G-S103A-V104I-A232V-Q245R-A272D、N018R-S024R-N076D-N116A-I198L-T213A-A215F-H249R、N018R-T22W-S024R-N076D-S101A-I198L-H249R、N018R-T022W-S024R-N076D-N116A-I198L-H249R、S024R-N076D-S101G-S103A-A232V、S024R-S103A-V104I、N018R-S024R-N076D-S101A-N116A-N183D-G211Q-A215F-H249R、S024R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、G020R-S101G-S103A-V104I-N116A-N183D-A232V-Q245R、S024R-N043D-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、G020R-T022W-S101A-S103A-V104I-N183D-G211Q-T213A-A215F-A232V-Q245R、G020R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-S024R-N076D-S101A-N116A-I198L-G211Q-A215F-H249R、G020R-S101A-S103A-V104I-N116A-N183D-A215F-A232V-Q245R、N018R-N043R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-S024R-N076D-I198L-T213A-H249R、N018R-S024R-N076D-N116A-N183D-T213A-H249R、G020R-N043D-S101G-S103A-V104I-A232V-Q245R-N269R、S024R-N076D-S103A-Q245R、N018R-T022W-S024R-N076D-S101A-N116A-G211Q-T213A-A215F-H249R、S103A-V104I-Q245R、N018R-T022W-S024R-N076D-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-N116A-N183D-I198L-H249R、N018R-T022W-S024R-N076D-I198L-G211Q-T213A-H249R、N018R-S024R-N076D-N116A-N183D-G211Q-T213A-A215F-H249R、N018R-G020R-N043D-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-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022W-S024R-N076D-N116A-A215F-H249R、N043R-N076D-S101G-S103T-V104I-A232V-Q245R-H249R-N269R、G020R-S078R-S101A-S103A-V104I-G115E-N116A-N183D-G211Q-T213A-A232V-Q245R、N018R-S024R-N076D-I198L-H249R、N018R-S024R-N076D-S101A-N116A-N183D-H249R、G020R-S101G-S103A-V104I-N116A-N183D-G211Q-A232V-Q245R、N018R-S024R-N076D-S101G、N076D-S101G-A232V-Q245R、N018R-N076D-S101G-S103A-V104I-Q245R、N018R-R045T-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-S024R-N076D-A215F-H249R、N018R-V104I-A232V、N043D-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、S024R-N076D-S101G-A232V-H249R、S103A-A232V-Q245R、G020R-S101G-S103A-V104I-N116A-N183D-G211Q-T213A-A215F-A232V-Q245R、N018R-G020R-S024R-N076D-N116A-N183D-I198L-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-S101A-I198L-G211Q-A215F-H249R、S024R-N076D-S103A-V104I-H249R、S024R-S101G-S103A-V104I、G020R-S101G-S103A-V104I-N116A-N183D-G211Q-A215F-A232V-Q245R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-A215F-H249R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-G211Q-T213A-A215F-A232V-Q245R、G020R-S024R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-N116A-N183D-T213A-H249R、N018R-G020R-S024R-N076D-A131T-A215F-H249R、N018R-S024R-N076D-S101A-N116A-N183D-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N116A-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-I198L-A215F-H249R、N018R-T022W-S024R-N076D-N183D-G211Q-H249R、N018R-T022W-S024R-N076D-S101A-N116A-T213A-A215F-H249R、N018R-G020R-S024R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N043R-S101G-S103A-V104I-Q245R-H249R、N018R-N076D-A232V-H249R、N018K-N076D-S078R-S101G-S103A-V104I-L217E-A232V-Q245R-N269R、N018R-G020R-S024R-N043D-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-S101A-N116A-T213A-A215F-H249R-L267I、A232V-H249R、N018R-G020R-S024R-N076D-N116A-G211Q-T213A-A215F-H249R、N076D-V104I-Q245R、N018R-G020R-S024R-N076D-N183D-I198L-G211Q-A215F-H249R、N018R-S024R-N076D-S101A-G211Q-T213A-H249R、S024R-S101G-S103A-A232V、N018R-G020R-T022W-S024R-N076D-N116A-N183D-I198L-T213A-A215F-H249R、N018R-G020R-S024R-N076D-N116A-N183D-I198L-G211Q-T213A-H249R、N018R-G020R-T022W-S024R-N076D-S101A-A215F-H249R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-G211Q-A215F-A232V-Q245R、N018R-S024R-N076D-N116A-I198L-G211Q-H249R、S103A-A232V-H249R、N018R-G020R-S024R-N076D-N116A-N183D-I198L-A215F-H249R、N018R-S024R-N076D-N116A-N183D-I198L-T213A-H249R、N018R-T022W-S024R-N076D-N183D-T213A-H249R、N018R-S024R-N076D-S101A-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-G211Q-H249R、N018R-R045T-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-G020R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-N116A-I198L-T213A-A215F-H249R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-G211Q-T213A-A232V-Q245R、N018R-G020R-S024R-N076D-I198L-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-G211Q-H249R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-A232V-Q245R-T274I、S024R-S103A-Q245R-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-H249R、N018R-S024R-N076D-S101A-I198L-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-N116A-I198L-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-T213A-H249R、N018R-N043D-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-T022W-S024R-N076D-N116A-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N183D-I198L-T213A-H249R、N043D-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-S024R-N076D-I198L-G211Q-T213A-A215F-H249R、N018R-G020R-S024R-N076D-N116A-N183D-T213A-H249R、S103A-A232V、N018R-T022W-S024R-N076D-N116A-N183D-A215F-H249R、N018R-S024R-N076D-S101A-N116A-H249R、N018R-N043R-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-S101A-N183D-G211Q-A215F-H249R、N043R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-I198L-T213A-H249R、N018R-S024R-N076D-N183D-I198L-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N183D-G211Q-H249R、N018R-G020R-S024R-N076D-I198L-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N183D-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-I198L-H249R、N018R-S024R-N076D-N183D-I198L-G211Q-H249R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-T213A-A232V-Q245R、N018R-G020R-S024R-N076D-N116A-N183D-G211Q-T213A-H249R、N018R-S024R-N076D-N116A-N183D-I198L-G211Q-T213A-A215F-H249R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-A215F-A232V-Q245R、N018R-S024R-N076D-S101A-N183D-H249R、N018R-S024R-N076D-A232V、N018R-T022W-S024R-N076D-S101A-N116A-H249R、G020R-S101A-S103A-V104I-N116A-N183D-I198L-G211Q-T213A-A215F-A232V-Q245R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-G211Q-A232V-Q245R-N263S、S024R-N076D-S101G-V104I-A232V-H249R、N043R-S078R-S101G-S103A-V104I-A232V-Q245R、S024R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-S024R-N076D-S101A-N183D-I198L-T213A-A215F-H249R、N018R-G020R-S024R-N076D-I198L-A215F-H249R、N018R-G020R-S024R-N076D-S101A-N116A-T213A-H249R、N018R-S024R-N076D-S101A-V197A-T213A-A215F-H249R、S024R-S101G-S103A、N018R-S024R-N076D-S101A-N116A-G211Q-A215F-H249R、N043R-N076D-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、S024R-V104I-A232V、N018R-S024R-N076D-N183D-G211Q-H249R、G020R-N043R-R045T-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-S101A-N11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-N076D-S101A-N183D-I198L-H249R、N043D-R045T-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-G020R-S024R-N076D-S101A-N183D-I198L-G211Q-H249R、N018R-G020R-N043R-S101G-S103A-V104I-L217E-A232V-Q245R、S024R-N043R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N043R-R045T-N076D-S078R-S101G-S103A-V104I-Y166F-A176P-A179V-N184T-A187P-A194P、N018R-T022W-S024R-D041E-N076D-S101A-S160T-N183D-G211Q-T213A-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-I198L-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-I198L-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-T213A-H249R、N018R-G020R-S024R-N076D-I198L-T213A-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-I198L-G211Q-H249R、N018R-G020R-S024R-N076D-N183D-G211Q-A215F-H249R、S024R-N076D-V104I、N018R-N076D-S101G-A232V、N018R-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-A215F-H249R、N018R-S024R-L031F-N076D-N116A-N183D-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N116A-N183D-I198L-T213A-H249R-N269S、N018R-G020R-S024R-N076D-S101A-N116A-I198L-A215F-H249R、N018R-N043R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-G020R-S024R-N076D-S101A-N114T-I198L-G211Q-A215F-H249R、S024R-N043R-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、S024R-N076D-S103A-V104I-A232V、N018R-G020R-T022W-S024R-N076D-S101A-I198L-G211Q-A215F-H249R、S101G-V104I-A232V、N018R-T022W-S024R-N076D-N183D-I198L-T213A-A215F-H249R、N018R-T022W-S024R-N076D-N183D-I198L-G211Q-H249R、N018R-G020R-S024R-N076D-N183D-T213A-H249R、N018R-S024R-N076D-S101A-N183D-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N116A-G211Q-T213A-H249R、N018R-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-G211Q-A215F-H249R-T260A、N076D-H249R、N018R-T022W-S024R-N076D-N183D-G211Q-A215F-H249R、N018R-G020R-S024R-N076D-N116A-G211Q-A215F-H249R、N018R-G020R-S024R-N076D-T213A-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-I198L-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N183D-H249R、N076D-V104I-H249R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-G211Q-T213A-A215F-A232V-Q245R、S024R-N043R-R045T-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-N183D-I198L-A215F-H249R、N018R-N076D-S101G-S103A、G020R-S024R-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-G211Q-H249R、S101G-S103A-A232V、S024R-N076D-S101G-A232V、N018R-T022W-S024R-N076D-S101A-N183D-I198L-G211Q-H249R、N018R-G020R-S024R-N076D-S101A-N183D-I198L-G211Q-A215F-H249R、N018R-G020R-S024R-N076D-N183D-I198L-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-H249R、N018R-G020R-S024R-N076D-N116A-A156V-N183D-G211Q-A215F-H249R-N269S、R045T-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-G020R-S024R-N076D-S101A-N183D-I198L-H249R、N018R-G020R-T022W-S024R-N076D-I198L-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-I198L-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N116A-H249R、N018R-N076D-S101G、N018R-S024R-N076D-N116A-N183D-I198L-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-I198L-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-H249R、N018R-N076D-A232V、N018R-G020R-S024R-N076D-S101A-A232V-Q245R、N018R-N043D-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-N183D-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N116A-G211Q-T213A-N237D-H249R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-G211Q-H249R-R275S、N018R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-T213A-A215F-H249R、S024R-N076D、N018R-S024R-N076D-N183D-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-N116A-N183D-I198L-T213A-A215F-H249R、N076D-V104I-A232V-H249R、N018R-N076D-S103A-A232V、N018R-G020R-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-T213A-H249R、N018R-G020R-S024R-N076D-S101A-N183D-T213A-H249R、N018R-G020R-S024R-N076D-S101A-D175E-N183D-G211Q-A215F-H249R、N018R-G020R-N043D-S078R-S101G-S103A-V104I-L217E-A232V-Q245R-A273E、G020R-S024R-N043D-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、P005S-S101G-S103A-V104I-A232V-Q245R-H249R、S103A-V104I-A232V、N018R-G020R-S024R-V068A-N076D-S101A-N116A-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-I198L-A215F-H249R-R275S、N018R-S024R-N076D-N183D-I198L-G211Q-T213A-H249R、及びN043D-R045T-S101G-S103A-V104I-A232V-Q245Rから選択されるアミノ酸置換の組み合わせを含むアミノ酸配列からなり、このサブチリシン変異体のアミノ酸位置は、配列番号1で示されるB.アミロリケファシエンスのサブチリシンBPN’のアミノ酸配列と対応させて番号付けされる、サブチリシン変異体を提供する。
別途記載のない限り、本発明の実施には、当該技術分野の範囲内のものである分子生物学、タンパク質工学、微生物学、及び組み換えDNAに一般的に使用される従来の技術を包含する。このような技術は当業者に既知のものであり、当業者に広く知られている数多くの文献及び参考文献に記載されている。本明細書で引用されるすべての特許、特許出願、論文及び刊行物は、参照により明示的に本案件に組み込まれる。
本発明は、総じて「本発明のポリペプチド」として参照することのできる新規ポリペプチドを提供する。本発明のポリペプチドとしては、単離された変異体プロテアーゼのポリペプチド、変異体プロテアーゼの組み換えポリペプチド、実質的に純粋な変異体プロテアーゼのポリペプチド又は非天然に生じる変異体プロテアーゼのポリペプチドが包含され、例えば、酵素活性(例えば、タンパク質分解活性)を有する変異体サブチリシンのポリペプチドが包含される。一部の実施形態では、本発明のポリペプチドは、クリーニング用途に有用であり、クリーニングされる必要のある物品又は表面(例えば、物品表面)のクリーニング方法に有用なクリーニング組成物に組み込むことができる。
AQSVPWGISRVQAPAAHNRGLTGSGVKVAVLDTGISTHPDLNIRGGASFVPGEPSTQDGNGHGTHVAGTIAALNNSIGVLGVAPSAELYAVKVLGASGSGSVSSIAQGLEWAGNNGMHVANLSLGSPSPSATLEQAVNSATSRGVLVVAASGNSGAGSISYPARYANAMAVGATDQNNNRASFSQYGAGLDIVAPGVNVQSTYPGSTYASLNGTSMATPHVAGAAALVKQKNPSWSNVQIRNHLKNTATSLGSTNLYGSGLVNAEAATR(配列番号2)である。
AQSVPYGVSQIKAPALHSQGYTGSNVKVAVIDSGIDSSHPDLKVAGGASMVPSETNPFQDNNSHGTHVAGTVAALNNSIGVLGVAPSASLYAVKVLGADGSGQYSWIINGIEWAIANNMDVINMSLGGPSGSAALKAAVDKAVASGVVVVAAAGNEGTSGSSSTVGYPGKYPSVIAVGAVDSSNQRASFSSVGPELDVMAPGVSIQSTLPGNKYGAYNGTSMASPHVAGAAALILSKHPNWTNTQVRSSLENTTTKLGDSFYYGKGLINVQAAAQ(配列番号1)である。
49R、X101G-X103A-X104I-X129E-X159E-X232V-X238R-X245R-X248D、X101G-X103A-X104I-X158E-X159E-X188D-X232V-X238R-X245R-X248D、X024R-X101G-X103A-X104I-X232V-X245R-X248D-X249R、X022A-X024R-X101G-X103A-X104I-X129E-X148I-X232V-X245R-X248D、X022A-X024R-X101G-X103A-X104I-X158E-X232V-X238R-X245R-X248D、X101G-X103A-X104I-X128N-X129E-X232V-X238R-X245R-X248D、X022A-X101G-X103A-X104I-X128N-X159E-X232V-X245R-X248D、X022A-X101G-X103A-X104I-X128N-X129E-X158E-X232V-X238R-X245R-X248D、X101G-X103A-X104I-X128N-X129E-X188D-X232V-X245R-X248D-X249R、X022A-X024R-X101G-X103A-X104I-X128N-X129E-X158E-X188D-X232V-X245R-X248D-X249R、X024R-X101G-X103A-X104I-X128N-X158E-X159E-X188D-X232V-X245R-X248D、X022A-X024K-X101G-X103A-X104I-X128N-X158E-X159E-X232V-X245R-X248D、X101G-X103A-X104I-X129E-X148I-X188D-X232V-X245R-X248D、X024R-X101G-X103A-X104I-X148I-X232V-X245R-X248D、X022A-X101G-X103A-X104I-X148I-X188D-X232V-X245R-X248D、X024R-X101G-X103A-X104I-X128N-X129E-X188D-X232V-X245R-X248D、X101G-X103A-X104I-X128N-X129E-X158E-X232V-X238R-X245R-X248D、X022A-X024R-X101G-X103A-X104I-X129E-X148I-X158E-X188D-X232V-X245R-X248D、X022A-X024R-X101G-X103A-X104I-X148I-X158E-X188D-X232V-X245R-X248D、X101G-X103A-X104I-X148I-X159E-X232V-X245R-X248D、X022A-X024R-X101G-X103A-X104I-X158E-X188D-X232V-X245R-X248D、及びX101G-X103A-X104I-X128N-X129E-X158E-X232V-X245R-X248D-X249Rから選択されるアミノ酸置換の組み合わせを含むアミノ酸配列からなり、このサブチリシン変異体のアミノ酸位置は、配列番号1で示されるB.アミロリケファシエンスのサブチリシンBPN’のアミノ酸配列と対応させて番号付けされる、サブチリシン変異体を提供する。
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-X076D-X101A-X183D-X198L-X249R、X043D-X045T-X101G-X103A-X104I-X232V-X245R-X269R、X018R-X020R-X024R-X076D-X101A-X183D-X198L-X211Q-X249R、X018R-X020R-X043R-X101G-X103A-X104I-X217E-X232V-X245R、X024R-X043R-X076D-X078R-X101G-X103A-X104I-X232V-X245R-X269R、X043R-X045T-X076D-X078R-X101G-X103A-X104I-X166F-X176P-X179V-X184T-X187P-X194P、X018R-X022W-X024R-X041E-X076D-X101A-X160T-X183D-X211Q-X213A-X249R、X018R-X020R-X022W-X024R-X076D-X116A-X183D-X198L-X211Q-X215F-X249R、X018R-X020R-X022W-X024R-X076D-X101A-X116A-X198L-X213A-X249R、X018R-X022W-X024R-X076D-X101A-X116A-X183D-X198L-X211Q-X213A-X249R、X018R-X020R-X024R-X076D-X198L-X213A-X249R、X018R-X020R-X022W-X024R-X076D-X116A-X183D-X198L-X211Q-X249R、X018R-X020R-X024R-X076D-X183D-X211Q-X215F-X249R、X024R-X076D-X104I、X018R-X076D-X101G-X232V、X018R-X024R-X076D-X101A-X116A-X183D-X198L-X211Q-X213A-X215F-X249R、X018R-X020R-X022W-X024R-X076D-X116A-X183D-X215F-X249R、X018R-X024R-X031F-X076D-X116A-X183D-X211Q-X213A-X215F-X249R、X018R-X024R-X076D-X101A-X116A-X183D-X198L-X213A-X249R-X269S、X018R-X020R-X024R-X076D-X101A-X116A-X198L-X215F-X249R、X018R-X043R-X076D-X078R-X101G-X103A-X104I-X232V-X245R-X269R、X018R-X020R-X024R-X076D-X101A-X114T-X198L-X211Q-X215F-X249R、X024R-X043R-X078R-X101G-X103A-X104I-X217E-X232V-X245R、X024R-X076D-X103A-X104I-X232V、X018R-X020R-X022W-X024R-X076D-X101A-X198L-X211Q-X215F-X249R、X101G-X104I-X232V、X018R-X022W-X024R-X076D-X183D-X198L-X213A-X215F-X249R、X018R-X022W-X024R-X076D-X183D-X198L-X211Q-X249R、X018R-X020R-X024R-X076D-X183D-X213A-X249R、X018R-X024R-X076D-X101A-X183D-X211Q-X215F-X249R、X018R-X020R-X022W-X024R-X076D-X116A-X211Q-X213A-X249R、X018R-X078R-X101G-X103A-X104I-X232V-X245R-X269R、X018R-X022W-X024R-X076D-X101A-X116A-X183D-X211Q-X215F-X249R-X260A、X076D-X249R、X018R-X022W-X024R-X076D-X183D-X211Q-X215F-X249R、X018R-X020R-X024R-X076D-X116A-X211Q-X215F-X249R、X018R-X020R-X024R-X076D-X213A-X249R、X018R-X020R-X022W-X024R-X076D-X116A-X183D-X198L-X249R、X018R-X020R-X022W-X024R-X076D-X101A-X183D-X249R、X076D-X104I-X249R、X020R-X022W-X101A-X103A-X104I-X116A-X183D-X211Q-X213A-X215F-X232V-X245R、X024R-X043R-X045T-X078R-X101G-X103A-X104I-X217E-X232V-X245R、X018R-X020R-X022W-X024R-X076D-X183D-X198L-X215F-X249R、X018R-X076D-X101G-X103A、X020R-X024R-X101G-X103A-X104I-X232V-X245R-X269R、X018R-X020R-X024R-X076D-X101A-X116A-X183D-X211Q-X249R、X101G-X103A-X232V、X024R-X076D-X101G-X232V、X018R-X022W-X024R-X076D-X101A-X183D-X198L-X211Q-X249R、X018R-X020R-X024R-X076D-X101A-X183D-X198L-X211Q-X215F-X249R、X018R-X020R-X024R-X076D-X183D-X198L-X249R、X018R-X022W-X024R-X076D-X101A-X116A-X183D-X198L-X211Q-X249R、X018R-X020R-X024R-X076D-X116A-X156V-X183D-X211Q-X215F-X249R-X269S、X045T-X076D-X101G-X103A-X104I-X232V-X245R-X249R、X018R-X020R-X024R-X076D-X101A-X183D-X198L-X249R、X018R-X020R-X022W-X024R-X076D-X198L-X211Q-X215F-X249R、X018R-X020R-X022W-X024R-X076D-X101A-X116A-X198L-X211Q-X215F-X249R、X018R-X020R-X022W-X024R-X076D-X116A-X249R、X018R-X076D-X101G、X018R-X024R-X076D-X116A-X183D-X198L-X213A-X215F-X249R、X018R-X020R-X022W-X024R-X076D-X101A-X116A-X198L-X213A-X215F-X249R、X018R-X024R-X076D-X101A-X116A-X183D-X198L-X211Q-X249R、X018R-X076D-X232V、X018R-X020R-X024R-X076D-X101A-X232V-X245R、X018R-X043D-X045T-X076D-X101G-X103A-X104I-X232V-X245R、X018R-X022W-X024R-X076D-X183D-X213A-X215F-X249R、X018R-X024R-X076D-X101A-X116A-X211Q-X213A-X237D-X249R、X018R-X020R-X024R-X076D-X101A-X116A-X183D-X211Q-X249R-X275S、X018R-X022W-X024R-X076D-X101A-X116A-X183D-X198L-X211Q-X213A-X215F-X249R、X024R-X076D、X018R-X024R-X076D-X183D-X211Q-X215F-X249R、X018R-X022W-X024R-X076D-X116A-X183D-X198L-X213A-X215F-X249R、X076D-X104I-X232V-X249R、X018R-X076D-X103A-X232V、X018R-X020R-X024R-X076D-X101A-X116A-X183D-X198L-X211Q-X213A-X249R、X018R-X020R-X024R-X076D-X101A-X183D-X213A-X249R、X018R-X020R-X024R-X076D-X101A-X175E-X183D-X211Q-X215F-X249R、X018R-X020R-X043D-X078R-X101G-X103A-X104I-X217E-X232V-X245R-X273E、X020R-X024R-X043D-X045T-X076D-X101G-X103A-X104I-X232V-X245R、X005S-X101G-X103A-X104I-X232V-X245R-X249R、X103A-X104I-X232V、X018R-X020R-X024R-X068A-X076D-X101A-X116A-X213A-X215F-X249R、X018R-X022W-X024R-X076D-X101A-X198L-X215F-X249R-X275S、X018R-X024R-X076D-X183D-X198L-X211Q-X213A-X249R、及びX043D-X045T-X101G-X103A-X104I-X232V-X245Rから選択されるアミノ酸置換の組み合わせを含むアミノ酸配列からなり、このサブチリシン変異体のアミノ酸位置は、配列番号1で示されるB.アミロリケファシエンスのサブチリシンBPN’のアミノ酸配列と対応させて番号付けされる、サブチリシン変異体を提供する。
49R、S101G-S103A-V104I-P129E-G159E-A232V-N238R-Q245R-N248D、S101G-S103A-V104I-A158E-G159E-S188D-A232V-N238R-Q245R-N248D、S024R-S101G-S103A-V104I-A232V-Q245R-N248D-H249R、T022A-S024R-S101G-S103A-V104I-P129E-L148I-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-A158E-A232V-N238R-Q245R-N248D、S101G-S103A-V104I-S128N-P129E-A232V-N238R-Q245R-N248D、T022A-S101G-S103A-V104I-S128N-G159E-A232V-Q245R-N248D、T022A-S101G-S103A-V104I-S128N-P129E-A158E-A232V-N238R-Q245R-N248D、S101G-S103A-V104I-S128N-P129E-S188D-A232V-Q245R-N248D-H249R、T022A-S024R-S101G-S103A-V104I-S128N-P129E-A158E-S188D-A232V-Q245R-N248D-H249R、S024R-S101G-S103A-V104I-S128N-A158E-G159E-S188D-A232V-Q245R-N248D、T022A-S024K-S101G-S103A-V104I-S128N-A158E-G159E-A232V-Q245R-N248D、S101G-S103A-V104I-P129E-L148I-S188D-A232V-Q245R-N248D、S024R-S101G-S103A-V104I-L148I-A232V-Q245R-N248D、T022A-S101G-S103A-V104I-L148I-S188D-A232V-Q245R-N248D、S024R-S101G-S103A-V104I-S128N-P129E-S188D-A232V-Q245R-N248D、S101G-S103A-V104I-S128N-P129E-A158E-A232V-N238R-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-P129E-L148I-A158E-S188D-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-L148I-A158E-S188D-A232V-Q245R-N248D、S101G-S103A-V104I-L148I-G159E-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-A158E-S188D-A232V-Q245R-N248D、及びS101G-S103A-V104I-S128N-P129E-A158E-A232V-Q245R-N248D-H249Rから選択されるアミノ酸置換の組み合わせを含むアミノ酸配列からなり、このサブチリシン変異体のアミノ酸位置は、配列番号1で示されるB.アミロリケファシエンスのサブチリシンBPN’のアミノ酸配列と対応させて番号付けされる、サブチリシン変異体を提供する。
45R、G020R-S101G-I198L-A215F-A232V-Q245R、N018R-S024R-N076D-T213A-A215F-H249R、G020R-S078R-S101G-S103A-V104I-N116A-G211Q-A232V-Q245R、G020R-T022W-S078R-S101A-S103A-V104I-N116A-N183D-A215F-A232V-Q245R、G020R-T022W-S078R-S101A-S103A-V104I-N116A-N183D-T213A-A232V-Q245R、S024R-A232V-Q245R、N018R-S024R-N043D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-S024R-N076D-S101A-A215F-H249R、N018R-T022W-S024R-N076D-N116A-T213A-H249R、S101G-S103A-V104I-A232V-Q245R、N018R-S024R-N076D-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-N116A-T213A-A215F-H249R、N043D-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N043D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、G020R-T022W-S078R-S101G-S103A-V104I-N116A-N183D-G211Q-A232V-Q245R、N018R-S024R-N076D-S101A-I198L-G211Q-A215V-H249R、N018R-T022W-S024R-N076D-N116A-G211Q-H249R、G020R-S103A-V104I-A232V-Q245R、G020R-T22W-S101A-S103A-V104I-G211Q-A215F-A232V-Q245R、S024R-N076D-S101G-S103A-V104I-A232V-Q245R、G020R-S101G-S103A-V104I-N116A-A232V-Q245R、N018R-T22W-S024R-N076D-I198L-A215F-H249R、G020R-T022W-S103A-V104I-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-G211Q-T213A-A232V-Q245R、G020R-T022W-S101G-S103A-V104I-G211Q-T213A-A215F-A232V-Q245R、N018R-N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-S101A-I198L-T213A-A215F-H249R、N018R-T22W-S024R-N076D-S101A-A215F-H249R、G020R-R045T-S101G-S103A-V104I-A232V-Q245R、G020R-S078R-S101G-S103A-V104I-T180A-A232V-Q245R、G020R-T022W-S078R-S101G-S103A-V104I-N116A-N183D-A215F-A232V-Q245R、N018R-S101G-S103A-V104I、G020R-T22W-S101A-S103A-V104I-N116A-G211Q-T213A-A215F-A232V-Q245R、N018R-S024R-N076D-S103A-A232V-Q245R、G020R-S078R-S101A-S103A-V104I-N116A-N183D-A232V-Q245R、N018R-S024R-N076D-G211Q-H249R、G020R-S101A-S103A-V104I-T213A-A215F-A232V-Q245R、N018R-G020R-N043D-S101G-S103A-V104I-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-G211Q-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-N116A-G211Q-A215F-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-N116A-G211Q-A232V-Q245R、N018R-S024R-N076D-A232V-H249R、N018R-S024R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-N076D-Q245R、S024R-V104I-Q245R、S101G-A232V、G020R-T22W-S101A-S103A-V104I-N116A-G211Q-A215F-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-I198L-T213A-H249R、G020R-T022W-S078R-S101A-S103A-V104I-A232V-Q245R、G020R-T022W-S078R-S101A-S103A-V104I-I198L-A232V-Q245R、S024R-Q245R-H249R、G020R-S101G-S103A-V104I-N116A-G211Q-A232V-Q245R、N018R-T22W-S024R-N076D-N116A-G211Q-H249R、S024R-S101G-V104I-H249R、N018R-S024R-N076D-N116A-I198L-G211Q-T213A-A215F-H249R、N018R-S024R-V104I、G020R-T022W-S078R-S101A-S103A-V104I-N183D-I198L-T213A-A215F-A232V-Q245R、N018R-G020R-T22W-S024R-N076D-N116A-N183D-I198L-T213A-H249R、G020R-T022W-S101A-S103A-V104I-A232V-Q245R、Q012H-G020R-S078R-S101G-S103A-V104I-I198L-G211Q-T213A-A232V-Q245R、N018R-S024R-N076D-S101A-G211Q-A215F-H249R、N018R-S024R-N076D-T213A-H249R、S024R-V104I-H249R、N018R-T022W-S024R-N076D-G211Q-H249R、N018R-N076D-S103A-V104I-H249R、N043R-N076D-S101G-S103A-V104I-L217E-A232V-Q245R、G020R-S078R-S101G-S103A-V104I-N183D-G211Q-T213A-A232V-Q245R-E271G、N018R-T022W-S024R-N076D-S101A-N116A-I198L-A215F-H249R、N018R-S024R-N043D-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-S024R-N076D-S101A-I198L-A215F-H249R、N018R-T022W-S024R-N076D-N116A-I198L-G211Q-T213A-H249R、N018R-S024R-N076D-S101A-N116A-T213A-A215F-H249R、G020R-N043D-R045T-S078R-S101G-S103A-V104I-A232V-Q245R、R045T-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-T22W-S024R-N076D-S101A-N116A-A215F-H249R、N043D-S101G-S103A-V104I-A232V-Q245R-N269R、G020R-T022W-S078R-S101A-S103A-V104I-N116A-N183D-T213A-A215F-A232V-Q245R、N018R-S024R-N076D-N116A-G211Q-T213A-A215F-H249R、S024R-S103A-M175L-A232V-H249R、N018R-S024R-N076D-N116A-T213A-H249R、G020R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、G020R-S078R-S101A-S103A-V104I-N116A-N183D-G211Q-T213A-A215F-A232V-Q245R、S024R-N043R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-S024R-N076D-S101A-N116A-I198L-T213A-A215F-H249R、N043R-R045T-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-S101A-I198L-G211Q-Q245R、G020R-S024R-N043D-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、S024R-A232V、G020R-S078R-S101A-S103A-V104I-N116A-N183D-G211Q-A232V-Q245R、S024R-N076D-S101G-A232V-Q245R、N018R-N076D-S101G-S103A-V104I-H249R、N018R-S024R-N076D-I198M-G211Q-T213A-A215F-H249R、N018R-T22W-S024R-N076D-S101A-I198L-A215F-H249R、N018R-N043R-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、G020R-T022W-S103A-G211Q-T213A-A215F-A232V-Q245R、G020R-S078R-S101A-S103A-V104I-N116A-N183D-G211Q-T213A-A232V-Q245R、R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-T22W-S024R-N076D-S101A-G211Q-T213A-H249R、N018R-S024R-N076D-N116A-I198L-A215F-H249R-V268G、N018R-T022W-S024R-N076D-S101A-G211Q-H249R、N018R-T022W-S024R-N076D-S101A-N116A-I198L-G211Q-H249R、S101G-S103A-V104I-Q245R、N018R-N076D-S101G-A232V-Q245R、N018R-G020R-R045T-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-S101A-N116A-I198L-H249R、N018R-T022W-S024R-N076D-N116A-I198L-T213A-H249R、S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、G020R-N043R-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-N043D-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、R045T-S101G-S103A-V104I-A232V-Q245R-N269R、S024R-S103A-A232V、N018R-S024R-N076D-S10
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-H249R、N018R-T022W-S024R-N076D-S101A-N116A-G211Q-T213A-H249R、N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-N076D-S101G-V104I-H249R、N018R-T022W-S024R-N076D-S101A-T213A-A215F-H249R、N018R-T22W-S024R-N076D-S101A-N116A-I198L-A215F-H249R、N018R-G020R-S101G-S103A-V104I-A232V-Q245R-H249R、S101G-S103A-V104I-A232V-Q245R-H249R-N269R、S024R-N076D-Q245R、N018R-G020R-N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-S024R-N076D-A215F-H249R、N018R-S024R-N076D-S101A-N116A-N183D-I198L-T213A-H249R、N018R-G020R-S024R-N076D-G211Q-A215F-H249R、N043D-S101G-S103A-V104I-A232V-Q245R、G020R-T22W-S078R-S101A-S103A-V104I-N116A-N183D-A215F-A232V-Q245R、N018R-S024R-N076D-I198L-G211Q-A215F-H249R、N043R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N043R-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、G020R-N043D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-T022W-S024R-N076D-S101A-T213A-H249R、G020R-T022W-S101A-N116A-I198L-G211Q-T213A-A215F-H249R、N043R-R045T-S078R-S101G-S103A-V104I-N218S-A232V-Q245R、N018R-S103A、G020R-T22W-S101G-S103A-V104I-N116A-N183D-A215F-A232V-Q245R、N018R-S024R-N076D-S101A-H249R、N018R-T022W-S024R-N076D-G211Q-T213A-H249R、S024R-N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-A232V-Q245R、G020R-S101A-S103A-V104I-N116A-N183D-G211Q-T213A-A215F-A232V-Q245R、K027R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、G020R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-G020R-S024R-N076D-N116A-N183D-T213A-A215F-H249R、N018R-S024R-N076D-V104I、S101G-S103A-V104I-A232V-H249R、N018R-S024R-N076D-N116A-N183D-G211Q-H249R、N018R-G020R-S024R-N076D-N116A-A215F-H249R、N018R-S024R-N076D-N183D-T213A-A215F-H249R、N018R-T022W-S024R-N076D-I198L-G211Q-H249R、N043D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R-R275S、G020R-T022W-S101A-S103A-V104I-N116A-N183D-G211Q-A232V-Q245R、N018R-T022W-S024R-N076D-S101A-I198L-G211Q-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-I198L-G211Q-T213A-A215F-H249R、N018R-G020R-S024R-N076D-N183D-H249R、N018R-S024R-N076D-N116A-I198L-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N116A-G211Q-H249R、V004M-N018R-S024R-N076D-N116A-I198L-G211Q-T213A-H249R、V104I-A232V-H249R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-G211Q-A215F-A232V-Q245R、G020R-S101A-S103A-V104I-N116A-N183D-G211Q-A232V-Q245R-T274I、G020R-S101A-S103A-V104I-T213A-A232V-Q245R、G020R-S101G-S103A-V104I-N116A-N183D-G211Q-T213A-A232V-Q245R、G020R-S024R-N043D-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-S024R-N076D-S103A-H249R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-G211Q-A215F-H249R、N018R-G020R-S024R-N076D-N116A-N183D-I198L-H249R、N018R-T022W-S024R-N076D-N116A-I198L-A215F-H249R、N018R-S024R-N076D-S101A-G211Q-T213A-A215F-H249R-A270V、N018R-N043D-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、G020R-T022W-S101G-S103A-V104I-N183D-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-T213A-H249R、N018R-T022W-S024R-N076D-I198L-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-I198L-T213A-H249R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-A232V-Q245R、N018R-T22W-S024R-N076D-N116A-I198L-T213A-H249R、N043R-R045T-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-S024R-N076D-S101G-S103A-V104I-A232V、S101G-H249R、S024R-N076D-S101G-S103A-V104I-M175L-H249R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-A232V-Q245R-N269S、N018R-S024R-N076D-S101A-N116A-I198L-H249R、N018R-T022W-S024R-N076D-N116A-H249R、N018R-G020R-S024R-N076D-S101A-N183D-I198L-A215F-H249R、N018R-S024R-N076D-T213A-A215F-H249R-T260K、N018R-S024R-N076D-N116A-G211Q-T213A-H249R、N018R-G020R-T022W-S024R-N076D-N116A-I198L-H249R、S024R-N076D-S101G-S103A-V104I-Q245R、S024R-N076D-S103A-H249R、N018R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-S024R-N076D-I198L-G211Q-H249R、N018R-T022W-S024R-N076D-S101A-I198L-G211Q-T213A-H249R、G020R-S024R-R045T-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-S024R-N076D-N183D-G211Q-T213A-H249R、N018R-N043D-R045T-S078R-S101G-S103A-V104I-A232V-Q245R-A272D、N018R-S024R-N076D-N116A-I198L-T213A-A215F-H249R、N018R-T22W-S024R-N076D-S101A-I198L-H249R、N018R-T022W-S024R-N076D-N116A-I198L-H249R、S024R-N076D-S101G-S103A-A232V、S024R-S103A-V104I、N018R-S024R-N076D-S101A-N116A-N183D-G211Q-A215F-H249R、S024R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、G020R-S101G-S103A-V104I-N116A-N183D-A232V-Q245R、S024R-N043D-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、G020R-T022W-S101A-S103A-V104I-N183D-G211Q-T213A-A215F-A232V-Q245R、G020R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-S024R-N076D-S101A-N116A-I198L-G211Q-A215F-H249R、G020R-S101A-S103A-V104I-N116A-N183D-A215F-A232V-Q245R、N018R-N043R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-S024R-N076D-I198L-T213A-H249R、N018R-S024R-N076D-N116A-N183D-T213A-H249R、G020R-N043D-S101G-S103A-V104I-A232V-Q245R-N269R、S024R-N076D-S103A-Q245R、N018R-T022W-S024R-N076D-S101A-N116A-G211Q-T213A-A215F-H249R、S103A-V104I-Q245R、N018R-T022W-S024R-N076D-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-N116A-N183D-I198L-H249R、N018R-T022W-S024R-N076D-I198L-G211Q-T213A-H249R、N018R-S024R-N076D-N116A-N183D-G211Q-T213A-A215F-H249R、N018R-G020R-N043D-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-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022W-S024R-N076D-N116A-A215F-H249R、N043R-N076D-S101G-S103T-V104I-A232V-Q245R-H249R-N269R、G020R-S078R-S101A-S103A-V104I-G115E-N116A-N183D-G211Q-T213A-A232V-Q245R、N018R-S024R-N076D-I198L-H249R、N018R-S024R-N076D-S101A-N116A-N183D-H249R、G020R-S101G-S103A-V104I-N116A-N183D-G211Q-A232V-Q245R、N018R-S024R-N076D-S101G、N076D-S101G-A232V-Q245R、N018R-N076D-S101G-S103A-V104I-Q245R、N018R-R045T-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-S024R-N076D-A215F-H249R、N018R-V104I-A232V、N043D-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、S024R-N076D-S101G-A232V-H249R、S103A-A232V-Q245R、G020R-S101G-S103A-V104I-N116A-N183D-G211Q-T213A-A215F-A232V-Q245R、N018R-G020R-S024R-N076D-N116A-N183D-I198L-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-S101A-I198L-G211Q-A215F-H249R、S024R-N076D-S103A-V104I-H249R、S024R-S101G-S103A-V104I、G020R-S101G-S103A-V104I-N116A-N183D-G211Q-A215F-A232V-Q245R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-A215F-H249R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-G211Q-T213A-A215F-A232V-Q245R、G020R-S024R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-N116A-N183D-T213A-H249R、N018R-G020R-S024R-N076D-A131T-A215F-H249R、N018R-S024R-N076D-S101A-N116A-N183D-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N116A-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-I198L-A215F-H249R、N018R-T022W-S024R-N076D-N183D-G211Q-H249R、N018R-T022W-S024R-N076D-S101A-N116A-T213A-A215F-H249R、N018R-G020R-S024R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N043R-S101G-S103A-V104I-Q245R-H249R、N018R-N076D-A232V-H249R、N018K-N076D-S078R-S101G-S103A-V104I-L217E-A232V-Q245R-N269R、N018R-G020R-S024R-N043D-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-S101A-N116A-T213A-A215F-H249R-L267I、A232V-H249R、N018R-G020R-S024R-N076D-N116A-G211Q-T213A-A215F-H249R、N076D-V104I-Q245R、N018R-G020R-S024R-N076D-N183D-I198L-G211Q-A215F-H249R、N018R-S024R-N076D-S101A-G211Q-T213A-H249R、S024R-S101G-S103A-A232V、N018R-G020R-T022W-S024R-N076D-N116A-N183D-I198L-T213A-A215F-H249R、N018R-G020R-S024R-N076D-N116A-N183D-I198L-G211Q-T213A-H249R、N018R-G020R-T022W-S024R-N076D-S101A-A215F-H249R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-G211Q-A215F-A232V-Q245R、N018R-S024R-N076D-N116A-I198L-G211Q-H249R、S103A-A232V-H249R、N018R-G020R-S024R-N076D-N116A-N183D-I198L-A215F-H249R、N018R-S024R-N076D-N116A-N183D-I198L-T213A-H249R、N018R-T022W-S024R-N076D-N183D-T213A-H249R、N018R-S024R-N076D-S101A-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-G211Q-H249R、N018R-R045T-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-G020R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-N116A-I198L-T213A-A215F-H249R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-G211Q-T213A-A232V-Q245R、N018R-G020R-S024R-N076D-I198L-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-G211Q-H249R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-A232V-Q245R-T274I、S024R-S103A-Q245R-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-H249R、N018R-S024R-N076D-S101A-I198L-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-N116A-I198L-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-T213A-H249R、N018R-N043D-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-T022W-S024R-N076D-N116A-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N183D-I198L-T213A-H249R、N043D-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-S024R-N076D-I198L-G211Q-T213A-A215F-H249R、N018R-G020R-S024R-N076D-N116A-N183D-T213A-H249R、S103A-A232V、N018R-T022W-S024R-N076D-N116A-N183D-A215F-H249R、N018R-S024R-N076D-S101A-N116A-H249R、N018R-N043R-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-S101A-N183D-G211Q-A215F-H249R、N043R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-I198L-T213A-H249R、N018R-S024R-N076D-N183D-I198L-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N183D-G211Q-H249R、N018R-G020R-S024R-N076D-I198L-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N183D-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-I198L-H249R、N018R-S024R-N076D-N183D-I198L-G211Q-H249R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-T213A-A232V-Q245R、N018R-G020R-S024R-N076D-N116A-N183D-G211Q-T213A-H249R、N018R-S024R-N076D-N116A-N183D-I198L-G211Q-T213A-A215F-H249R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-A215F-A232V-Q245R、N018R-S024R-N076D-S101A-N183D-H249R、N018R-S024R-N076D-A232V、N018R-T022W-S024R-N076D-S101A-N116A-H249R、G020R-S101A-S103A-V104I-N116A-N183D-I198L-G211Q-T213A-A215F-A232V-Q245R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-G211Q-A232V-Q245R-N263S、S024R-N076D-S101G-V104I-A232V-H249R、N043R-S078R-S101G-S103A-V104I-A232V-Q245R、S024R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-S024R-N076D-S101A-N183D-I198L-T213A-A215F-H249R、N018R-G020R-S024R-N076D-I198L-A215F-H249R、N018R-G020R-S024R-N076D-S101A-N116A-T213A-H249R、N018R-S024R-N076D-S101A-V197A-T213A-A215F-H249R、S024R-S101G-S103A、N018R-S024R-N076D-S101A-N116A-G211Q-A215F-H249R、N043R-N076D-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、S024R-V104I-A232V、N018R-S024R-N076D-N183D-G211Q-H249R、G020R-N043R-R045T-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-S101A-N11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24R-N076D-N116A-N183D-I198L-G211Q-H249R、N018R-S024R-N076D-S101G-Q245R、N018R-S024R-N076D-S101A-N116A-N183D-I198L-T213A-A215F-H249R、N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-N116A-I198L-T213A-A215F-H249R、N076D-V104I-A232V-Q245R、K027R-N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-S101A-N183D-T213A-A215F-H249R、N018R-S024R-N076D-S103A-V104I-L135I-A232V、N018R-G020R-T022W-S024R-N076D-N183D-I198L-G211Q-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-A215F-H249R、N018R-S024R-N076D-S101A-N116A-N183D-G211Q-H249R、N018R-T022W-S024R-N076D-N183D-G211Q-T213A-A215F-H249R、N076D-S101G-S103A-V104I-A232V-H249R、P005S-N018R-T022W-S024R-N076D-S101A-T213A-A215F-H249R、N018R-S024R-N076D-N116A-N183D-A215F-H249R、N018R-S024R-N076D-N183D-I198L-A215F-H249R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-H249R、N018R-T022W-S024R-N076D-N116A-N183D-G211Q-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N183D-G211Q-T213A-H249R、N018R-G020R-S024R-N076D-N116A-I198L-H249R、N018R-S024R-N076D-N183D-G211Q-T213A-H249R、N018R-S024R-N076D-S101A-N116A-N183D-T213A-H249R、N018R-S024R-N076D-N116A-N183D-I198L-A215F-H249R、N018R-T022W-S024R-N076D-N183D-I198L-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-N183D-H249R、N018R-T022W-S024R-N076D-S101A-N183D-I198L-A215F-H249R、N018R-G020R-N043D-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-N183D-I198L-A215F-A232V-Q245R、N076D-S101G-S103A-V104I-H249R、N018R-G020R-S024R-N076D-N183D-I198L-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N183D-A215F-H249R、N018R-G020R-S024R-N076D-G211Q-T213A-H249R、N018R-S024R-N076D-N116A-N183D-G211Q-T213A-H249R、N018R-S024R-N076D-N116A-N183D-I198L-H249R、N018R-G020R-S024R-N076D-G211Q-N243D-H249R、N018R-G020R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-T022W-S024R-N076D-N183D-I198L-G211Q-T213A-H249R、N018R-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-N116A-I198L-G211Q-T213A-A215F-H249R、S024R-N076D-S101G、N018R-G020R-S024R-N076D-S101A-I198L-T213A-A215F-H249R、N018R-T022W-S024R-N076D-N116A-N183D-G211Q-T213A-H249R、N018R-G020R-S024R-N076D-N183D-A215F-H249R、N018R-N043D-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-T022W-S024R-N076D-N116A-N183D-G211Q-T213A-Q245R、G020R-S024R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-G020R-R045T-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-S024R-N076D-S101A-N183D-I198L-G211Q-H249R、N018R-T022W-S024R-N076D-N183D-G211Q-T213A-H249R、N018R-G020R-S024R-N076D-N116A-I198L-G211Q-A215F-H249R-N269S、N018R-G020R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-A215F-H249R、G020R-T022W-S101A-S103A-V104I-N183D-T213A-A215F-A232V-Q245R、N018R-S024R-N076D-A086V-S101A-N183D-I198L-G211Q-H249R、N018R-N076D-S101G-I198T-A232V、N018R-G020R-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N183D-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-N183D-H249R-A248T、N018R-N076D-V104I-Q245R-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-A215F-H249R、N018R-T022W-S024R-N076D-N116A-N183D-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-G211Q-T213A-A215F-H249R、N018R-G020R-S024R-N076D-S101A-H249R、N018R-G020R-S024R-N076D-S101A-N116A-T213A-A215F-H249R、N018R-T022W-S024R-N076D-N116A-N183D-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-N116A-N183D-I198L-G211Q-T213A-H249R、N043R-R045T-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、N043R-R045T-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-N076D-S101G-V104I、G020R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N043D-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-H249R、N018R-N076D-V104I、N018R-G020R-N043D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-G020R-T022W-S024R-N076D-N183D-G211Q-H249R、N018R-S024R-N076D-S101A-N183D-I198L-G211Q-A215F-H249R、S101G-V104I、N018R-T022W-S024R-N076D-N116A-N183D-I198L-G211Q-T213A-A215F-H249R、N018R-G020R-S024R-N076D-S101A-N183D-G211Q-T213A-A215F-H249R、N018R-G020R-S024R-N076D-N116A-N183D-A215F-H249R-N263D、N018R-T022W-S024R-N076D-S101A-N183D-H249R、N018R-S024R-N076D-S101A-N116A-N183D-I198L-A215F-H249R、N018R-T022W-S024R-N076D-N116A-I198L-A215F-H249R-R269H、N018R-N043D-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-S024R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、S078R-S101G-S103A-V104I-L217E-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-S101A-N183D-I198L-T213A-A215F-H249R、N018R-G020R-S024R-N076D-N183D-I198L-T213A-H249R、N018R-G020R-T022W-S024R-N076D-N116A-I198L-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-G211Q-H249R、N018R-G020R-T022W-S024R-N076D-S101A-I198L-G211Q-T213A-H249R、N018R-G020R-T022W-S024R-N076D-H249R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-I198L-G211Q-T213A-A215F-A232V-Q245R、V104I-A232V、N018R-G020R-T022W-S024R-N076D-S101A-N116A-N183D-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N183D-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N183D-I198L-G211Q-T213A-H249R、N018R-T022W-S024R
-N076D-S101A-N183D-I198L-H249R、N043D-R045T-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-G020R-S024R-N076D-S101A-N183D-I198L-G211Q-H249R、N018R-G020R-N043R-S101G-S103A-V104I-L217E-A232V-Q245R、S024R-N043R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N043R-R045T-N076D-S078R-S101G-S103A-V104I-Y166F-A176P-A179V-N184T-A187P-A194P、N018R-T022W-S024R-D041E-N076D-S101A-S160T-N183D-G211Q-T213A-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-I198L-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-I198L-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-T213A-H249R、N018R-G020R-S024R-N076D-I198L-T213A-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-I198L-G211Q-H249R、N018R-G020R-S024R-N076D-N183D-G211Q-A215F-H249R、S024R-N076D-V104I、N018R-N076D-S101G-A232V、N018R-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-A215F-H249R、N018R-S024R-L031F-N076D-N116A-N183D-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N116A-N183D-I198L-T213A-H249R-N269S、N018R-G020R-S024R-N076D-S101A-N116A-I198L-A215F-H249R、N018R-N043R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-G020R-S024R-N076D-S101A-N114T-I198L-G211Q-A215F-H249R、S024R-N043R-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、S024R-N076D-S103A-V104I-A232V、N018R-G020R-T022W-S024R-N076D-S101A-I198L-G211Q-A215F-H249R、S101G-V104I-A232V、N018R-T022W-S024R-N076D-N183D-I198L-T213A-A215F-H249R、N018R-T022W-S024R-N076D-N183D-I198L-G211Q-H249R、N018R-G020R-S024R-N076D-N183D-T213A-H249R、N018R-S024R-N076D-S101A-N183D-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N116A-G211Q-T213A-H249R、N018R-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-G211Q-A215F-H249R-T260A、N076D-H249R、N018R-T022W-S024R-N076D-N183D-G211Q-A215F-H249R、N018R-G020R-S024R-N076D-N116A-G211Q-A215F-H249R、N018R-G020R-S024R-N076D-T213A-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-I198L-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N183D-H249R、N076D-V104I-H249R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-G211Q-T213A-A215F-A232V-Q245R、S024R-N043R-R045T-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-N183D-I198L-A215F-H249R、N018R-N076D-S101G-S103A、G020R-S024R-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-G211Q-H249R、S101G-S103A-A232V、S024R-N076D-S101G-A232V、N018R-T022W-S024R-N076D-S101A-N183D-I198L-G211Q-H249R、N018R-G020R-S024R-N076D-S101A-N183D-I198L-G211Q-A215F-H249R、N018R-G020R-S024R-N076D-N183D-I198L-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-H249R、N018R-G020R-S024R-N076D-N116A-A156V-N183D-G211Q-A215F-H249R-N269S、R045T-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-G020R-S024R-N076D-S101A-N183D-I198L-H249R、N018R-G020R-T022W-S024R-N076D-I198L-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-I198L-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N116A-H249R、N018R-N076D-S101G、N018R-S024R-N076D-N116A-N183D-I198L-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-I198L-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-H249R、N018R-N076D-A232V、N018R-G020R-S024R-N076D-S101A-A232V-Q245R、N018R-N043D-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-N183D-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N116A-G211Q-T213A-N237D-H249R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-G211Q-H249R-R275S、N018R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-T213A-A215F-H249R、S024R-N076D、N018R-S024R-N076D-N183D-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-N116A-N183D-I198L-T213A-A215F-H249R、N076D-V104I-A232V-H249R、N018R-N076D-S103A-A232V、N018R-G020R-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-T213A-H249R、N018R-G020R-S024R-N076D-S101A-N183D-T213A-H249R、N018R-G020R-S024R-N076D-S101A-D175E-N183D-G211Q-A215F-H249R、N018R-G020R-N043D-S078R-S101G-S103A-V104I-L217E-A232V-Q245R-A273E、G020R-S024R-N043D-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、P005S-S101G-S103A-V104I-A232V-Q245R-H249R、S103A-V104I-A232V、N018R-G020R-S024R-V068A-N076D-S101A-N116A-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-I198L-A215F-H249R-R275S、N018R-S024R-N076D-N183D-I198L-G211Q-T213A-H249R、及びN043D-R045T-S101G-S103A-V104I-A232V-Q245Rから選択されるアミノ酸置換の組み合わせを含むアミノ酸配列からなり、このサブチリシン変異体のアミノ酸位置は、配列番号1で示されるB.アミロリケファシエンスのサブチリシンBPN’のアミノ酸配列と対応させて番号付けされる、サブチリシン変異体を提供する。
a)G020K-G023A-N043W-G118R-S128I-P129E-G159D-S188D、G020K-G023A-N062E-N116L、G020K-G023A-N062E-N116L-S188D、G020K-G023A-N062E-N116L-S188D-T213A、G020K-G100S-N116L-A158E-S166D-N243F、G020K-N043W-N062E-N116L-S188D、G020K-N062E、G020K-N062E-N116L、G020K-N062E-N116L-S188D、G020K-N062E-N116L-T213A、G020K-N062E-S188D-T213A、G020K-S024F-N062E-N116L-G118R-S188D、G020K-S024F-N062E-N116L-S188D、G020K-S024F-N062E-S188D-T213A、G023A-N062E-N116L-S188D、G023A-S024F-N062E-N116L-T213A、N043R-N076D-S101A-S103A-V104I-A158E-S188D-L217E-A232V-Q245R-N248D-H249R-E271F、N043R-S101A-S103A-V104I-A158E-S188D-L217E-A232V-Q245R-N248D-H249R、N043W-N062E-N116L、N043W-S101D-S212M-N243F、N062E-N116L-G118R-S188D、N062E-N116L-G118R-T213A、N062E-N116L-S188D-T213A、S024F-G118R-S128I-P129E-G159D、S024F-N062E-N116L-S188D、S024R-S101G-S103A-V104I-A158E-N183D-S188D-A232V-Q245R-N248D-H249R、S024R-S101G-S103A-V104I-A158E-S188D-A232V-Q245R-N248D-H249R、S024R-S101G-S103A-V104I-A158E-S188D-L217E-A232V-Q245R-N248D-H249R、S024R-S101G-S103A-V104I-P129Q-A158E-N183D-S188D-A232V-Q245R-N248D-H249R、S024R-S101G-S103A-V104I-P129Q-A158E-S188D-A232V-Q245R-N248D-H249R、S024R-S101G-S103A-V104I-P129Q-A158E-S188D-L217E-A232V-Q245R-N248D-H249R、S024R-S101G-S103A-V104I-P129Q-S130A-A158E-N183D-S188D-A232V-Q245R-N248D-H249R、S024R-S101G-S103A-V104I-S128L-P129Q-A158E-S188D-A232V-Q245R-N248D-H249R、S024R-S101G-S103A-V104I-S130A-A158E-N183D-S188D-A232V-Q245R-N248D-H249R、S024R-S101G-S103A-V104I-S130A-A158E-S188D-A232V-Q245R-N248D-H249R、S101D-S103N-N116L-S144R-A215D、S101G-S103A-V104I-A158E-S188D-A232V-Q245R-N248D-H249R、S101G-S103A-V104I-S130A-A158E-S188D-A232V-Q245R-N248D-H249R、T022A-N043R-S101G-S103A-V104I-G159D-S188D-L217E-A232V-Q245R-N248D-E271F、T022A-N043R-S103A-V104I-G118R-S128I-P129E-G159D-S188D-A232V-N248D-E271F、T022A-N043R-S103A-V104I-S128I-P129E-G159D-S188D-A232V-Q245R-N248D、T022A-S024R-S103A-V104I-G118R-S128I-P129E-G159D-S188D-A232V-N248D、T022A-S101G-S103A-V104I-G159D-L217E-A232V-Q245R-N248D-E271F、T022A-S101G-S103A-V104I-G159D-S188D-A232V-Q245R-N248D-E271F、T022L-T038F-A048R-N062E-G100S-R186K、T033S-N043W-N218D-P239G-N243F、V026F-A048R-S105T-T213A-N218D-T224A、V026F-L031F-S078N-G102A-S160D、V026F-V051W-V104L-S106E、V104L-S105T-T213A-L217E-S256N、A016S-N062E-A158E-H249R、A016S-N062E-A158E-R186H-E271F、A016S-N062E-A158E-R186H-H249R、A016S-N062E-V104L-A158E-R186H-E271F、A016S-S024R-S101G-S103A-V104I-A158E-S188D-A232V-Q245R-N248D-H249R、G020K-G023A-N062E-S188D、G020K-G023A-S024F-N062E-G118R-S188D-T213A、G020K-N043W-N062E-N116L-S188D-T213A-P239G、G020K-S024F-N062E-S188D-P239G、G023A-N062E-N116L-G118R、G023A-N062E-N116L-G118R-S188D-P239G、G023A-S024F-N062E-N116L-G118R、H017R-T022A-N076D-S101G-S103A-V104I-G159D-S188D-A232V-Q245R-N248D-E271F、N043R-N076D-S101A-S103A-V104I-A158E-S188D-A232V-Q245R-N248D-H249R-E271F、N062E-A158E-G159E-H249R、N062E-A158E-H249R、N062E-A158E-R186H-E271F、N062E-A158E-R186H-H249R、N062E-A158E-R186H-H249R-E271F、N062E-A158E-S188D-H249R、N062E-A158E-S188D-H249R-E271F、N062E-G159E-H249R、N062E-G159E-H249R-E271F、N062E-G159E-R186H-H249R、N062E-G159E-S188D-H249R、N062E-R186H-S188D-H249R-E271F、N062E-S101A-A158E-H249R、N062E-S101A-A158E-R186H-E271F、N062E-S101A-A158E-R186H-H249R-E271F、N062E-S101A-G159E-H249R、N062E-S101A-R186H-H249R、N062E-S101A-S188D-H249R、N062E-S101A-S188D-H249R-E271F、N062E-S101A-V104L-A158E-R186H-E271F、N062E-S128N-A158E-G159E-E271F、N062E-V104L-A158E-S188D-H249R-E271F、N076D-S101G-S103A-V104I-A232V-M222Q-Q245R、S024F-N062E-N116L-P239G、S024F-N062E-S188D-T213A、S024F-N116L、S024R-N043R-N076D-S101A-S103A-V104I-A158E-S188D-L217E-A232V-Q245R-N248D-H249R、S024R-S101G-S103A-V104I-A158E-G159E-A232V-N238R-Q245R-N248D、S024R-S101G-S103A-V104I-A158E-G159E-S188D-A232V-Q245R-N248D、S024R-S101G-S103A-V104I-A158E-S188D-A232V-N238R-Q245R-N248D、S024R-S101G-S103A-V104I-A232V-Q245R-N248D-H249R、S024R-S101G-S103A-V104I-G159E-S188D-A232V-N238R-Q245R-N248D、S024R-S101G-S103A-V104I-G159E-S188D-A232V-Q245R-N248D、S024R-S101G-S103A-V104I-G159E-S188D-A232V-Q245R-N248D-H249R、S024R-S101G-S103A-V104I-L148I-A158E-A232V-Q245R-N248D、S024R-S101G-S103A-V104I-L148I-A158E-S188D-A232V-Q245R-N248D、S024R-S101G-S103A-V104I-L148I-A232V-Q245R-N248D、S024R-S101G-S103A-V104I-P129E-A158E-A232V-Q245R-N248D-H249R、S024R-S101G-S103A-V104I-P129E-A158E-G159E-S188D-A232V-Q245R-N248D-H249R、S024R-S101G-S103A-V104I-P129E-A158E-S188D-A232V-Q245R-N248D、S024R-S101G-S103A-V104I-P129E-A158E-S188D-A232V-Q245R-N248D-H249R、S024R-S101G-S103A-V104I-P129E-G159E-A232V-Q245R-N248D、S024R-S101G-S103A-V104I-P129E-G159E-S188D-A232V-Q245R-N248D-H249R、S024R-S101G-S103A-V104I-P129E-L148I-A158E-A232V-Q245R-N248D、S024R-S101G-S103A-V104I-P129E-S188D-A232V-N238R-Q245R-N248D、S024R-S101G-S103A-V104I-P129E-S188D-A232V-Q245R-N248D、S024R-S101G-S103A-V104I-P129E-S188D-A232V-Q245R-N248D-H249R、S024R-S101G-S103A-V104I-S128N-A158E-A232V-Q245R-N248D、S024R-S101G-S103A-V104I-S128N-P129E-A158E-A232V-Q245R-N248D-H249R、S024R-S101G-S103A-V104I-S128N-P129E-A232V-Q245R-N248D、S101A-S103A-V104I-A158E-S188D-A232V-Q245R-N248D-H249R、S101A-S103A-V104I-A158E-S188D-A232V-Q245R-N248D-H249R-E271F-E271F、S101A-S103A-V104L-A158E-S188D-A232V-Q245R-N248D-H249R、S101A-S128N-A158E-R186H-E271F、S101A-S128N-A158E-Y209E-H249R、S101A-V104L-A158E-R186H-
S188D-H249R、S101G-S103A-V104I-A158E-A232V-Q245R-N248D-H249R、S101G-S103A-V104I-A158E-G159E-A232V-Q245R-N248D-H249R、S101G-S103A-V104I-A158E-S188D-M222Q-A232V-Q245R-N248D-H249R、S101G-S103A-V104I-A158E-S188D-M222S-A232V-Q245R-N248D-H249R、S101G-S103A-V104I-A232V-M222Q-Q245R、S101G-S103A-V104I-P129E-A158E-S188D-A232V-Q245R-N248D-H249R、S101G-S103A-V104I-P129E-G159E-A232V-Q245R-N248D-H249R、S101G-S103A-V104I-P129E-S188D-A232V-N238R-Q245R-N248D、S101G-S103A-V104I-P129E-S188D-A232V-Q245R-N248D-H249R、S101G-S103A-V104I-S188D-A232V-Q245R-N248D-H249R、S101G-S103G-V104I-A158E-S188D-A232V-Q245R-N248D-H249R、S101G-S103S-V104I-A158E-S188D-A232V-Q245R-N248D-H249R、S101S-S103A-V104I-A158E-S188D-A232V-Q245R-N248D-H249R、S101S-S103G-V104I-A158E-S188D-A232V-Q245R-N248D-H249R、S101S-S103G-V104V-A158E-S188D-A232V-Q245R-N248D-H249R、S128N-A158E-G159E-E271F、S128N-A158E-H249R、S128N-A158E-R186H-E271F、S128N-A158E-R186H-H249R、S128N-A158E-R186H-S188D-E271F、S128N-A158E-S188D-E271F、S128N-A158E-S188D-H249R、S128N-A158E-S188D-Y209E-E271F、S128N-A158E-Y209E-、T022A-N043R-S103A-V104I-G118R-P129E-G159D-S188D-A232V-Q245R-N248D、T022A-N062E-A158E、T022A-S024R-S101D-S103A-V104I-G118R-G159D-S188D-A232V-N248D-E271F、T022A-S024R-S101D-S103A-V104I-G118R-P129E-G159D-S188D-A232V-Q245R-N248D、T022A-S024R-S101D-S103A-V104I-G159D-S188D-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-A158E-A232V-N238R-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-A158E-A232V-Q245R-N248D-H249R、T022A-S024R-S101G-S103A-V104I-A158E-G159E-S188D-A232V-N238R-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-A158E-G159E-S188D-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-A158E-G159E-S188D-A232V-Q245R-N248D-H249R、T022A-S024R-S101G-S103A-V104I-P129E-A158E-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-P129E-A158E-A232V-Q245R-N248D-H249R、T022A-S024R-S101G-S103A-V104I-P129E-A158E-G159E-A232V-Q245R-N248D-H249R、T022A-S024R-S101G-S103A-V104I-P129E-A158E-G159E-S188D-A232V-N238R-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-P129E-A158E-S188D-A232V-N238R-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-P129E-A158E-S188D-A232V-Q245R-N248D-H249R、T022A-S024R-S101G-S103A-V104I-P129E-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-P129E-A232V-Q245R-N248D-H249R、T022A-S024R-S101G-S103A-V104I-P129E-G159E-S188D-A232V-Q245R-N248D-H249R、T022A-S024R-S101G-S103A-V104I-P129E-S188D-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-S128N-A158E-S188D-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-S128N-P129E-A158E-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-S128N-P129E-S188D-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-S128N-S188D-A232V-Q245R-N248D、T022A-S024R-S103A-V104I-G118R-G159D-S188D-L217D-A232V-N248D、T022A-S024R-S103A-V104I-P129E-G159D-S188D-A232V-N248D-E271F、T022A-S101G-S103A-V104I-A158E-G159E-S188D-A232V-Q245R-N248D-H249R、T022A-S101G-S103A-V104I-A158E-S188D-A232V-Q245R-N248D、T022A-S101G-S103A-V104I-P129E-A158E-A232V-N238R-Q245R-N248D、T022A-S101G-S103A-V104I-P129E-A158E-G159E-A232V-N238R-Q245R-N248D、T022A-S101G-S103A-V104I-P129E-A158E-S188D-A232V-Q245R-N248D-H249R、T022A-S101G-S103A-V104I-P129E-G159E-A232V-N238R-Q245R-N248D、T022A-S101G-S103A-V104I-P129E-S188D-A232V-N238R-Q245R-N248D、T022A-S101G-S103A-V104I-S128N-P129E-A232V-N238R-Q245R-N248D、T022A-S101G-S103A-V104I-S128N-P129E-S188D-A232V-N238R-Q245R-N248D、T022A-S128N-A158E-H249R、V104L-S128N-A158E-H249R、V104L-S128N-A158E-R186H-E271F、V104L-S128N-A158E-R186H-H249R、及び/又はV104L-S128N-A158E-S188D-H249R;
b)A016S-N062E-A158E-H249R-E271F、A016S-N062E-S128N-R186H-E271F、A016S-N062E-V104L-R186H-S188D-E271F、A016S-S101A-S128N-R186H、A016S-S128N-A158E-R186H、A016S-V104L-A158E-R186H-E271F、A016S-V104L-S188D-H249R、A158E-R186H-H249R、A158E-R186H-S188D-H249R-E271F、G020K-G023A-N116L-S188D、G020K-G023A-S024F-N062E-N116L-S188D-T213A、G020K-N043W-N062E-N116L-P239G、G020K-S024F-N043W-N062E-N116L-T213A、G020K-S024F-N062E、G023A-N043W-N062E-N116L-G118R-T213A、G023A-T038F-S078N-G100S-S212M-A215D、G100S-N116L-A158E-T213A、G102A-S103N-S105T-A194E、H017R-T022A-N076D-S101G-S103A-V104I-G159D-A232V-Q245R-N248D-E271F、N043R-N076D-S101A-S103A-V104I-A158E-S166D-S188D-A232V-Q245R-N248D-H249R-E271F、N043R-S101A-S103A-V104I-A158E-S166D-S188D-A232V-Q245R-N248D-H249R、N043W-N062E-N116L-S188D、N062E-A158E-H249R-E271F、N062E-A158E-R186H-S188D-H249R、N062E-L148I-G159E、N062E-N116L-S188D、N062E-R186H-H249R、N062E-S078N-G102A-N116L-S144R-L250I、N062E-S101A-A158E-R186H-H249R、N062E-S101A-A158E-S188D-H249R、N062E-S101A-R186H、N062E-S101A-R186H-E271F、N062E-S101A-R186H-H249R-E271F、N062E-S101A-R186H-S188D-E271F、N062E-S101A-R186H-S188D-H249R、N062E-S101A-V104L-R186H-S188D-E271F、N062E-S128N-A158E、N062E-S128N-G159E-H249R、N062E-S188D-P239G、N062E-V104L-G159E-H249R、N076D-S101A-S103A-V104I-A158E-S166D-S188D-A232V-Q245R-N248D-H249R-E271F、N076D-S101A-S103A-V104I-A158E-S188D-A232V-Q245R-N248D-H249R、N076D-S101A-S103A-V104I-A158E-S188D-A232V-Q245R-N248D-H249R-E271F、N076D-S101G-S103A-V104I-A114V-A158E-S188D-A232V-Q245R-N248D-H249R-E271F、N076D-S101G-S103A-V104I-A232V-M222S-Q245R、S024F-A048R-G118R-S166D-L217E、S024F-N062E-N116L、S024F-N062E-N116L-T213A-P239G、S024F-N062E-S188D-P239G、S024F-S101D-G118R-A215D-L250I-A272F、S024R-K027R-S101G-S103A-V104I-S128L-P129Q-S130A-A158E-S188D-A232V-Q245R-N248D-H249R、S024R-N076D-S101A-S103A-V104I-A158E-S166D-S188D-A232V-Q245R-N248D-H249R-E271F、S024R-S101G-S103A-V104I-A158E-A232V-Q245R-N248D-H249R、S024R-S101G-S103A-V104I-P129E-A158E-G159E-A232V-N238R-Q245R-N248D、S024R-S101G-S103A-V104I-P129E-A158E-G159E-A232V-Q245R-N248D-H249R、S024R-S101G-S103A-V104I-P129E-G159E-A232V-N238R-Q245R-N248D、S024R-S101G-S103A-V104I-P129E-G159E-S188D-A232V-N238R-Q245R-N248D、S024R-S101G-S103A-V104I-P129E-L148I-A158E-S188D-A232V-Q245R-N248D、S024R-S101G-S103A-V104I-P129E-L148I-S188D-A232V-Q245R-N248D、S024R-S101G-S103A-V104I-P129Q-S130A-A158E-S188D-A232V-Q245R-N248D-H249R、S024R-S101G-S103A-V104I-S128L-A158E-S188D-A232V-Q245R-N248D-H249R、S024R-S101G-S103A-V104I-S128L-P129Q-S130A-A158E-S188D-A232V-Q245R-N248D-H249R、S024R-S101G-S103A-V104I-S128N-G159E-S188D-A232V-Q245R-N248D、S078N-V104L-G118R-S128D、S101A-A158E-R186H-H249R、S101A-A158E-R186H-S188D-H249R、S101A-S103A-V104I-A158E-S166D-S188D-A232V-Q245R-N248D-H249R-E271F、S101A-S103A-V104I-A158E-S188D-A232V-Q245R-N248D-H249R-E271F、S101A-S103A-V104I-A158E-S188D-L217E-A232V-Q245R-N248D-H249R、S101A-S103A-V104I-A158E-S188D-L217E-A232V-Q245R-N248D-H249R-E271F、S101A-S103G-A158E-R186H-H249R、S101A-S103S-V104I-A158E-S188D-A232V-Q245R-N248D-H249R、S101A-S103S-V104I-G159E-A232V-Q245R-N248D-H249R、S101A-S128N-A158E-H249R、S101A-S128N-A158E-S188D-Y209E-E271F、S101A-S128N-A158E-Y209E、S101A-S128N-P129E-R186H-H249R、S101A-V104L-A158E-R186H-H249R、S101A-V104L-A158E-R186H-S188D-E271F、S101A-V104L-S128N-A158E-R186H-E271F、S101G-S103A-V104I-A158E-A232V-N238R-Q245R-N248D、S101G-S103A-V104I-A158E-G159E-S188D-A232V-N238R-Q245R-N248D、S101G-S103A-V104I-A158E-N183D-S188D-A232V-Q245R-N248D-H249R、S101G-S103A-V104I-A158E-S166D-S188D-A232V-Q245R-N248D-H249R-E271F、S101G-S103A-V104I-A158E-S188D-A232V-Q245R-N248D、S101G-S103A-V104I-A232V-M222S-Q245R、S101G-S103A-V104I-P129E-A158E-G159E-A232V-N238R-Q245R-N248D、S101G-S103A-V104I-P129E-A158E-G159E-A232V-Q245R-N248D-H249R、S101G-S103A-V104I-P129E-A158E-S188D-A232V-N238R-Q245R-N248D、S101G-S103A-V104I-P129E-G159E-A232V-N238R-Q245R-N248D、S101G-S103A-V104I-P129E-S188D-A232V-Q245R-N248D、S101G-S103A-V104I-P129Q-A158E-S188D-A232V-Q245R-N248D-H249R、S101G-S103A-V104I-P129Q-S130A-A158E-S188D-A232V-Q245R-N248D-H249R、S101G-S103A-V104I-S128L-P129Q-A158E-S188D-A232V-Q245R-N248D-H249R、S101G-S103A-V104I-S128L-S130A-A158E-S188D-L217E-A232V-Q245R-N248D-H249R、S101G-S103A-V104I-S128N-P129E-A232V-N238R-Q245R-N248D、S101G-S103A-V104I-S128N-P129E-A232V-Q245R-N248D、S101G-S103A-V104I-S130A-A158E-N183D-S188D-L217E-A232V-Q245R-N248D-H249R、S101G-S103A-V104I-S188D-A232V-N238R-Q245R-N248D、S101G-S103A-V104L-A158E-S188D-A232V-Q245R-N248D-H249R、S101S-S103A-V104I-G159E-A232V-Q245R-N248D-H249R、S101S-S103S-V104I-A158E-S188D-A232V-Q245R-N248D-H249R、S101S-S103S-V104V-A158E-S188D-A232V-Q245R-N248D-H249R、T022A-N043R-N062E-S103A-V104I-G159D-S188D-A232V-Q245R-N248D-E271F、T022A-N043R-N076D-S101G-S103A-V104I-G159D-S188D-A232V-Q245R-N248D-E271F、T022A-N043R-S101D-S103A-V104I-G118R-P129E-G159D-S188D-A232V-N248D-E271F、T022A-N043R-S101G-S103A-V104I-G159D-A232V-Q245R-N248D-E271F、T022A-N043R-S103A-V104I-G118R-G159D-S188D-A232V-N248D-E271F、T022A-N043R-S103A-V104I-G118R-G159D-S188D-L217D-A232V-N248D-E271F、T022A-N043R-S103A-V104I-G118R-S128I-P129E-G159D-S188D-A232V-N248D、T022A-N043R-S103A-V104I-P129E-G159D-S188D-A232V-Q245R-N248D、T022A-N076D-S101G-S103A-V104I-G159D-A232V-Q245R-N248D-E271F、T022A-N076D-S101G-S103A-V104I-
G159D-S188D-A232V-Q245R-N248D-E271F、T022A-S024R-N043R-S101D-S103A-V104I-G159D-S188D-A232V-Q245R-N248D、T022A-S024R-N043R-S103A-V104I-G159D-S188D-L217D-A232V-N248D-E271F、T022A-S024R-S101D-S103A-V104I-G118R-S128I-G159D-S188D-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-L148I-A158E-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-P129E-A158E-G159E-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-P129E-A158E-G159E-S188D-A232V-Q245R-N248D-H249R、T022A-S024R-S101G-S103A-V104I-P129E-L148I-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-S188D-A232V-Q245R-N248D-H249R、T022A-S024R-S103A-V104I-G118R-P129E-G159D-S188D-A232V-N248D-E271F、T022A-S024R-S103A-V104I-G159D-S188D-L217D-A232V-N248D-E271F、T022A-S024R-S103A-V104I-G159D-S188D-L217D-A232V-Q245R-N248D-E271F、T022A-S101A-A158E-R186H-H249R、T022A-S101G-S103A-V104I-A158E-G159E-A232V-N238R-Q245R-N248D、T022A-S101G-S103A-V104I-A158E-G159E-A232V-Q245R-N248D-H249R、T022A-S101G-S103A-V104I-G159D-A232V-Q245R-N248D-E271F、T022A-S101G-S103A-V104I-G159D-S188D-A232V-Q245R-N248D-H249R-E271F、T022A-S101G-S103A-V104I-G159E-S188D-A232V-N238R-Q245R-N248D、T022A-S101G-S103A-V104I-G159E-S188D-A232V-Q245R-N248D-H249R、T022A-S101G-S103A-V104I-P129E-A158E-A232V-Q245R-N248D-H249R、T022A-S101G-S103A-V104I-P129E-A158E-G159E-A232V-Q245R-N248D-H249R、T022A-S101G-S103A-V104I-P129E-A232V-N238R-Q245R-N248D、T022A-S101G-S103A-V104I-P129E-G159E-A232V-Q245R-N248D-H249R、T022A-S101G-S103A-V104I-P129E-G159E-S188D-A232V-Q245R-N248D-H249R、T022A-S103A-V104I-G118R-G159D-S188D-L217D-A232V-Q245R-N248D、T022A-S103A-V104I-G159D-S188D-A232V-N248D、T022L-L031F-G102A-S128D-T224A-N243F、T022L-T038F-V121F-S160D-A272F、V026F-S078N-G159C-R186K-N243F、V104L-A158E-H249R、V104L-A158E-R186H-H249R、V104L-A158E-R186H-H249R-E271F、V104L-A158E-R186H-S188D-H249R、V104L-A158E-R186H-S188D-H249R-E271F、V104L-A158E-S188D-H249R-E271F、V104L-S128N-A158E-R186H-S188D-E271F、V104L-S128N-G159E-E271F、V104L-S128N-R186H-S188D-H249R、及び/又はV121F-N185E-T224A-P239G;
c)A016S-S128N-R186H-E271F、N076D-S101G-S103A-V104I-A158E-S188D-M222S-A232V-Q245R-N248D-H249R、S024R-S101G-S103A-V104I-S128L-P129Q-A158E-N183D-S188D-A232V-Q245R-N248D-H249R、S024R-S101G-S103A-V104I-S128L-P129Q-A158E-S188D-A232V-Q245R-N248D-H249R-E271G、S024R-S101G-S103A-V104I-S128L-P129Q-S130A-A158E-N183D-S188D-A232V-Q245R-N248D-H249R、S101G-S103A-V104I-P129Q-A158E-N183D-S188D-A232V-Q245R-N248D-H249R、T022A-N076D-S101G-S103A-V104I-G159D-A232V-Q245R-N248D-H249R-E271F、T022A-S101G-G102A-S103A-V104I-G159D-S188D-A232V-Q245R-N248D-E271F、A016S-A158E-H249R、A016S-A158E-H249R-E271F、A016S-A158E-R186H-H249R、A016S-L111V-S188D-、A016S-T022A-A158E-R186H-E271F、A048R-S078N-N116L-N185E-L217E-P239G、A048R-S128D-N185E-P239G、A158E-R186H-H249R-E271F、E089P-S101A-P129E-R186H、G020K-G023A-N043W-N116L-S188D-T213A-P239G、G020K-G023A-N062E-N116L-G118R-T213A、G020K-G023A-S024F-N062E-S188D-T213A-P239G、G020K-K027R-P129E-S166D-P239G、G020K-S024F-N062E-P239G、G020K-S024F-T033S-P129E-A194E、G023A-G100S-A194E-S212M、G023A-N043W-N116L-G118R-S188D、G023A-S024F-G118R-S188D-P239G、G023A-S024F-K027R-N062E、G023A-S024F-N043W-N062E-N116L-G118R、G023A-S024F-N116L-G118R-S188D-T213A、G023A-S024F-N116L-S188D-P239G、K027R-G100S-G118R-S160D-S188D-N243F、K027R-S101D-S103N-S105T-A272F、N043R-N076D-S101A-S103A-V104I-A158E-S166D-S188D-A232V-Q245R-N248D-H249R、N062E-S078N-N116L-T224A、N062E-V104L-A158E-R186H-S188D-H249R、N076D-S101A-S103A-V104I-A158E-S188D-L217E-A232V-Q245R-N248D-H249R-E271F、N076D-S101G-S103A-V104I-A158E-S166D-S188D-A232V-Q245R-N248D-H249R-E271F、S024F-G102A-R186K-T213A-L217E-N243F、S024F-N043W-G118R-S188D、S024F-N043W-V104L-V121F-P129E、S024F-N116L-G118R-S188D-P239G、S024F-S103N-V104L-G118R-S188D、S024R-N043R-S101A-S103A-V104I-A158E-S188D-A232V-Q245R-N248D-H249R、S024R-N043R-S101A-S103A-V104I-A158E-S188D-L217E-A232V-Q245R-N248D-H249R、S024R-N076D-S101G-S103A-V104I-A158E-S188D-A232V-Q245R-N248D-H249R-E271F、S024R-S101G-S103A-V104I-A158E-G159E-A232V-Q245R-N248D、S024R-S101G-S103A-V104I-S128N-A158E-G159E-S188D-A232V-Q245R-N248D、S024R-S101G-S103A-V104I-S128N-P129E-S188D-A232V-Q245R-N248D、S101A-L111V-P129E、S101A-S103A-V104L-G159E-A232V-Q245R-N248D-H249R、S101A-S103S-V104L-G159E-A232V-Q245R-N248D-H249R、S101A-V104L-S128N-A158E-R186H、S101G-S103A-V104I-P129E-L148I-S188D-A232V-Q245R-N248D、S101G-S103A-V104I-S128N-P129E-A158E-A232V-N238R-Q245R-N248D、S101G-S103A-V104I-S128N-P129E-S188D-A232V-Q245R-N248D-H249R、S101G-S103S-V104L-G159E-A232V-Q245R-N248D-H249R、S101S-S103A-V104L-G159E-A232V-Q245R-N248D-H249R、S128N-P129E-R186H、T022A-A158E-R186H-H249R-E271F、T022A-S024K-S101G-S103A-V104I-S128N-A158E-G159E-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-S128N-P129E-A158E-S188D-A232V-Q245R-N248D-H249R、T022A-S024R-S103A-V104I-S128I-G159D-S188D-A232V-N248D、T022A-S101G-S103A-V104I-L148I-S188D-A232V-Q245R-N248D、T022A-S101G-S103A-V104I-S128N-G159E-A232V-Q245R-N248D、T022A-S101G-S103A-V104I-S128N-P129E-A158E-A232V-N238R-Q245R-N248D、T022A-S128N-A158E-R186H、T022A-S128N-R186H-S188D-、T022A-V104L-A158E-H249R、T022A-V104L-R186H-S188D-H249R、T022L-G023A-K027R-S101D-V104L-S216F、T022L-S078N-N116L-P129E-S256N、T022L-S078N-S128D-T213A、T033S-G118R-P129E-A194E-P239G、T033S-S105T-S188D-S216F、V026F-V104L-S256N-A272F、T022A-N043R-S103A-V104I-S128I-G159D-S188D-A232V-Q245R-N248D、T022A-S024R-N043R-S103A-V104I-G118R-G159D-S188D-L217D-A232V-N248D、T022A-S101D-S103A-V104I-G118R-G159D-S188D-L217D-A232V-Q245R-N248D-E271F、T022A-S103A-V104I-G118R-P129E-G159D-S188D-A232V-Q245R-N248D-E271F、T022A-S103A-V104I-G159D-S188D-L217D-A232V-Q245R-N248D-E271F、及び/又はT022A-S103A-V104I-S128I-P129E-G159D-S188D-A232V-N248D-E271F;
d)G118R-Y209A、G118R-Y209A-N243F、L021M-S024R-T033S、P005S-S078R-G118R-W241R、P086W-G118R-A133V、P086W-G118R-N243F、P086W-G118R-Y209A、P086W-Y209A-N243F、S024R-A174T、S024R-G118R、S024R-G118R-Y209A、S024R-G118R-Y209A-K235F、S024R-G118R-Y209A-N243F、S024R-K235F、S024R-P086R、S024R-P086S-S141G、S024R-P086W、S024R-P086W-G118R、S024R-P086W-G118R-V203I、S024R-P086W-N243F、S024R-P086W-Y209A、S024R-S078R-P086W、S024R-S078R-P086W-G118R-A270T、S024R-S078R-P086W-N243F、S024R-T033S-A133V、S024R-T033S-G118R、S024R-T033S-P086S-S085N-K235F、S024R-T033S-P086S-S087N-Y209A、S024R-T033S-P086W、S024R-T033S-P086W-G118R、S024R-T033S-S078R-P086W、S024R-T033S-S078R-P086W-G118R、S024R-T033S-S078R-Y209A、S024R-T033S-W241R、S024R-T033S-Y209A-K235F、S024R-Y209A-W241R、S078R-G118R、S078R-P086W-K235F、S078R-P086W-N243F、S078R-P086W-Y209A、S078R-Y209A-K235F、T033S-A172V-Y209A、T033S-G118R、T033S-G118R-G159D-Y209A、T033S-G118R-N243F、T033S-G118R-W241R、T033S-G118R-Y209A-N243F、T033S-K235F、T033S-P086W-G118R、T033S-P086W-G118R-Y209A-N243F、T033S-P086W-N243F、T033S-S078R-P086W、T033S-S078R-P086W-G118R-Y209A、T033S-S078R-Y209A、T033S-Y209A-N243F、Y209A-W241R、A001R-S009A-N043R、A001R-S101G-S103A-V104I-A232V-Q245R、A001T-N018R-S024R-N076D-N116A-T213A-H249R、A194F-G211Q-Q236N、E089I-N116A-N117F-T224A-H249R、G020R-G025R-N116A-Y167W、G020R-H249R-N269R、G020R-N043D-N076D-A230E-H249R、G020R-N043D-S078R-S101G-S103A-V104I-A232V-Q245R、G020R-N043D-S101G-S103A-V104I-A232V-Q245R、G020R-N043D-S101G-S103A-V104I-A232V-Q245R-N269R、G020R-N043R-A230E、G020R-N043R-A230E-S242R、G020R-N043R-E271L、G020R-N043R-H249R、G020R-N043R-H249R-E271L、G020R-N043R-N269R、G020R-N043R-R045T-A230E、G020R-N043R-R045T-S101A-N269R、G020R-N043R-R045T-S242R、G020R-N043R-S101A-N116A-T213A-A215F、G020R-N043R-S101A-N269R、G020R-N043R-S101G-S103A-V104I-A232V-Q245R、G020R-N043R-S212F、G020R-N043R-S212F-W241R、G020R-N043R-S242R、G020R-N043R-S242R-E271L、G020R-N043R-S242R-H249R、G020R-N043R-V244R、G020R-N043R-W241R、G020R-N062Q-E089I-R186K-S212M、G020R-N076D、G020R-N076D-S101G-S103A-V104I-A232V-Q245R、G020R-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、G020R-N116A-N269R、G020R-P052N-N062Q-Y091F-Y192W、G020R-Q059A-S144R-Y192W-T224A、G020R-S024R-K27E-N043R-N076D-A230E、G020R-S024R-N043D-H249R、G020R-S024R-N043D-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、G020R-S024R-N043D-S242R、G020R-S024R-N043R-R045T、G020R-S024R-N043R-R045T-H249R、G020R-S024R-N043R-R045T-N116A、G020R-S024R-N043R-R045T-N116A-T213A、G020R-S024R-N043R-R045T-S101A-N269R、G020R-S024R-N043R-R045T-S101A-T213A、G020R-S024R-N043R-S242R、G020R-S024R-N076D-H249R、G020R-S024R-N116A、G020R-S024R-N116A-A215F、G020R-S024R-N116A-T213A、G020R-S024R-N116A-T213A-A215F、G020R-S024R-P052N-Q059A-S216F、G020R-S024R-R045T-A230E-S242R、G020R-S024R-R045T-N116A-N269R、G020R-S024R-R045T-N269R、G020R-S024R-S101A-A215F、G020R-S024R-S101A-N116A、G020R-S024R-S101G-S103A-V104I-L217E-A232V-Q245R-H249R、G020R-S024R-S242R-H249R、G020R-S024R-T213A、G020R-S024R-T213A-A215F、G020R-S078R-S101A-S103A-V104I-N116A-N183D-T213A-A232V-Q245R、G020R-S078R-S101G-A232V-Q245R、G020R-S078R-S101G-S103A-V104I-A215F-A232V-Q245R、G020R-S078R-S101G-S103A-V104I-G211Q-T213A-A215F-A232V-Q245R、G020R-S078R-S101G-S103A-V104I-N116A-A232V-Q245R、G020R-S078R-S101G-S103A-V104I-N116A-G211Q-A232V-Q245R、G020R-S078R-S101G-S103A-V104I-N116A-N183D-A232V-Q245R、G020R-S087D-S101G-S103A-V104I-A232V-Q245R、G020R-S101A-N116A-N269R、G020R-S101A-S103A-V104I-A215F-A232V-Q245R、G020R-S101A-S103A-V104I-G118R-A232V-Q245R、G020R-S101A-S103A-V104L-A232V-Q245R、G020R-S101A-S103A-V104V-A232V-Q245R、G020R-S101A-S103S-V104I-A232V-Q245R、G020R-S101A-S103S-V104V-A232V-Q245R、G020R-S101G-I198L-A215F-A232V-Q245R、G020R-S101G-S103A-A232V-Q245R、G020R-S101G-S103A-V104I-A215F-A232V-Q245R、G020R-S101G-S103A-V104I-A232V-Q245R、G020R-S101G-S103A-V104I-A232V-Q245R-N269R、G020R-S101G-S103A-V104I-G211Q-T213A-A215F-A232V-Q245R、G020R-S101G-S103A-V104I-N116A-A215F-A232V-Q245R、G020R-S101G-S103A-V104I-T213A-A215F-A232V-Q245R、G020R-S101G-S103A-V104I-V150L-A232V-Q245R、G020R-S101G-S103A-V104L-A232V-Q245R、G020R-S101G-S103A-V104V-A232V-Q245R、G020R-S101G-S103G-V104I-A232V-Q245R、G020R-S101G-S103S-V104I-A232V-Q245R、G020R-S101G-S103S-V104L-A232V-Q245R、G020R-S101G-V104I-T213A-A215F-A232V-Q245R、G020R-S101S-S103A-V104I-A232V-Q245R、G020R-S101S-S103A-V104V-A232V-Q245R、G020R-S101S-S103G-V104I-A232V-Q245R、G020R-S101S-S103G-V104V-A232V-Q245R、G020R-S101S-S103S-V104I-A232V-Q245R、G020R-S101S-S103S-V104L-A232V-Q245R、G020R-S101S-S103S-V104V-A232V-Q245R、G020R-S103N-S216F-Q236N-N252R、G020R-S144R-N185I-L233C-Q236N、G020R-S212F-H249R、G020R-S242R-N269R、G020R-T022R-E271L、G020R-T022R-N043R、G020R-T022R-N043R-S212F、G020R-T022R-N043R-W241R、G020R-T022R-S024R-S242R、G020R-T022R-S078R-S242R、G020R-T022R-S078R-W241R、G020R-T022R-S212F-W241R、G020R-T022R-S242R、G020R-T022R-W241R、G020R-T022W-S078R-S101A-S103A-V104I-N116A-N183D-A215F-A232V-Q245R、G020R-T022W-S078R-S101A-S103A-V104I-N116A-N183D-A232V-Q245R、G020R-T022W-S078R-S101A-S103A-V104I-N116A-N183D-T213A-A232V-Q245R、G020R-T022W-S078R-S101A-S103A-V104I-N116S-T213A-A215F-A232V-Q245R、G020R-T022W-S078R-S101G-S103A-V104I-N116A-A232V-Q245R、G020R-T022W-S078R-S101G-S103A-V104I-N116A-N183D-A232V-Q245R、G020R-T022W-S078R-S101G-S103A-V104I-N116A-N183D-G211Q-A232V-Q245R、G020R-T022W-S
078R-S101G-S103A-V104I-N116A-N183D-T213A-A232V-Q245R、G020R-T022W-S078R-S101G-S103A-V104I-N116A-T213A-A215F-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-G211Q-A215F-A232V-Q245R、G020R-T022W-S101G-S103A-V104I-A232V-Q245R、G020R-T022W-S101G-S103A-V104I-G211Q-A232V-Q245R、G020R-T022W-S101G-S103A-V104I-I198L-G211Q-T213A-A232V-Q245R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-T213A-A232V-Q245R、G020R-T038A-N043R-S101A、G020R-T22W-S078R-S101A-S103A-V104I-N116A-N183D-A232V、G020R-T22W-S078R-S101G-S103A-V104I-N116A-N183D-A232V-Q245R、G020R-T22W-S078R-S101G-S103A-V104I-N116A-T213A-A215F-A232V-Q245R、G020R-T22W-S101A-S103A-V104I-A215F-A232V-Q245R、G020R-T22W-S101A-S103A-V104I-A232V-Q245R、G020R-T22W-S101A-S103A-V104I-G211Q-T213A-A232V-Q245R、G020R-T22W-S101G-S103A-V104I-A232V-Q245R、G020R-T22W-S101G-S103A-V104I-G211Q-A232V-Q245R、G020R-T22W-S103A-V104I-A232V-Q245R、G023A-P052N-S144R-Y192W-S216F、G023A-P052N-Y192W-I198L-N252R、G023A-S024R-N117F-S212M-S216F、G023A-S078R-S216F-Q236N-H249R、G023A-Y091F-S101A-I198L-N252R、G023A-Y091F-V121F-Y192W-Q236N、G025R-E089I-N116A-P239S-A270C、G025R-G046R-V121F、G025R-N043A-E089I-N117F、G025R-S103N-R186K-A194F-T224A、G046R-A194F-S212M、G046R-E089I-Y091F-S101A-N116A、G046R-E089I-Y192W-L233C-A270C、G046R-N183D-N238L、G046R-Q059A-S103N-G211Q-S212M、G046R-Q059A-S106G-L217E-H249R、L148I-T213A-N252R、N018R-G020R-N043D、N018R-G020R-N043D-A230E-S242R、N018R-G020R-N043D-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-N043D-R045T-A230E、N018R-G020R-N043R-N076D-H249R、N018R-G020R-N043R-N076D-S242R-H249R、N018R-G020R-N043R-R045T-S242R、N018R-G020R-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-R045T、N018R-G020R-S024R-N043D-R045T-L233I-S242R、N018R-G020R-S024R-N043R-R045T-N076D-A230E、N018R-G020R-S024R-N076D-S087D-H249R、N018R-G020R-S024R-N076D-V150L-H249R、N018R-G020R-S024R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-N043D-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-N043D-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-N043D-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、N018R-N043D-S101G-S103A-V104I-A232V-Q245R、N018R-N043D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-N043D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-N043R-N076D-A230E、N018R-N043R-R045T-H249R、N018R-N043R-R045T-S101G-S103A-V104I-A232V-Q245R、N018R-N043R-R045T-S242R-H249R、N018R-N043R-S101G-S103A-V104I-A232V-Q245R、N018R-N043R-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-N043R-S242R-H249R、N018R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-N076D-S101G-V104I-A232V-Q245R、N018R-Q245R、N018R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-R045T-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-R045T-S101G-S103A-V104I-A232V-Q245R、N018R-S024R-N043D-A230E、N018R-S024R-N043D-N076D-H249R、N018R-S024R-N043D-N076D-H249R-N269R、N018R-S024R-N043D-N076D-S078R-H249R、N018R-S024R-N043D-R045T-H249R、N018R-S024R-N043D-S101G-S103A-V104I-A232V-Q245R、N018R-S024R-N043D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-S024R-N043R-N076D-H249R、N018R-S024R-N043R-N076D-H249R-N269R、N018R-S024R-N043R-N076D-S087D-H249R、N018R-S024R-N043R-N076D-V150L-H249R、N018R-S024R-N076D-G211Q-A215F-H249R、N018R-S024R-N076D-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-G211Q-T213A-H249R、N018R-S024R-N076D-H249R、N018R-S024R-N076D-H249R-N269R、N018R-S024R-N076D-N116A-A215F-H249R、N018R-S024R-N076D-N116A-G211Q-A215F-H249R、N018R-S024R-N076D-N116A-G211Q-H249R、N018R-S024R-N076D-N116A-T213A-A215F-H249R、N018R-S024R-N076D-S078R-H249R、N018R-S024R-N076D-S078R-S087D-H249R、N018R-S024R-N076D-S078R-V150L-H249R、N018R-S024R-N076D-S087D-H249R-N269R、N018R-S024R-N076D-S087D-S242R-H249R、N018R-S024R-N076D-S087D-V150L-H249R、N018R-S024R-N076D-S101A-A215F-H249R、N018R-S024R-N076D-S101A-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-S101A-I198L-G211Q-A215V-H249R、N018R-S024R-N076D-S101A-I198L-G211Q-T213A-H249R、N018R-S024R-N076D-S101A-N116A-G211Q-H249R、N018R-S024R-N076D-S101A-N116A-T213A-H249R、N018R-S024R-N076D-S101G-V104I-A232V-H249R、N018R-S024R-N076D-S242R-H249R、N018R-S024R-N076D-T213A-A215F-H249R、N018R-S024R-N076D-V104I-H249R、N018R-S024R-N076D-V150L-H249R、N018R-S024R-R045T-S242R、N018R-S024R-S101G-V104I、N018R-S024R-S101G-V104I-A232V、N018R-S024R-S242R、N018R-S024R-V104I-H249R、N018R-S024R-V244R、N018R-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-S087D-S101G-S103A-V104I-A232V-Q245R、N018R-S101G-Q245R、N018R-S101G-S103A-H249R、N018R-S101G-S103A-Q245R、N018R-S101G-S103A-V104I-A232V-Q245R、N018R-S101G-S103A-V104I-V150L-A232V-Q245R、N018R-S101G-V104I-A232V-H249R、N018R-S101G-V104I-A232V-Q245R、N018R-S101G-V104I-H249R、N018R-S103A-A232V-H249R、N018R-S103A-V104I-H249R、N018R-T022R-S024R-N043D-N076D-H249R、N018R-T022R-S024R-N043R-N076D-H249R、N018R-T022R-S024R-N076D-H249R、N018R-T022R-S024R-N076D-S087D-H249R、N018R-T022R-S024R-N076D-V150L-H249R、N018R-T022W-S024R-N076D-N116A-G211Q-H249R、N018R-T022W-S024R-N076D-N116A-T213A-H249R、N018R-T022W-S024R-N076D-S101A-I198L-A215F-H249R、N018R-T022W-S024R-N076D-S101A-I198L-H249R、N018R-T022W-S024R-N076D-S101A-N116A-A232V-Q245R、N018R-T22K-N043D-S101G-S103A-V104I-A232V-Q245R、N018R-T22W-S024R-N076D-N116A-T213A-H249R、N018R-T22W-S024R-N076D-S101A-N116A-A232V-Q245R、N018R-V104I-A232V-H249R、N043A-N062Q-A194F-G211Q、N043A-T057R-N117F-S144R-N183D、N043
D-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N043D-R045T-N076D-H249R、N043D-S078R-S101G-S103A-V104I-A232V-Q245R、N043D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N043D-S101G-S103A-V104I-A232V-Q245R-N269R、N043R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N043R-N076D-S101G-S103A-V104I-A232V-Q245R、N043R-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N043R-N076D-S242R-H249R、N043R-N116A-N269R、N043R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N043R-R045T-S078R-S101G-S103A-V104I-A232V-Q245R、N043R-R045T-S101G-S103A-V104I-A232V-Q245R-N269R、N043R-S078R-S101G-S103A-V104I-A232V-Q245R、N043R-S087D-S101G-S103A-V104I-A232V-Q245R-N269R、N043R-S101A-N116A-A215F-N269R、N043R-S101A-N116A-N269R、N043R-S101A-N116A-T213A-A215F-N269R、N043R-S101A-N269R、N043R-S101A-T213A-N269R、N043R-S101G-S103A-V104I-A232V-Q245R、N043R-S101G-S103A-V104I-A232V-Q245R-E271L、N043R-S101G-S103A-V104I-A232V-Q245R-H249R、N043R-S101G-S103A-V104I-A232V-Q245R-N269R、N043R-S101G-S103A-V104I-A232V-S242R-Q245R、N043R-S101G-S103A-V104I-V150L-A232V-Q245R、N043R-S242R-H249R、N043R-T213A-A215F-N269R、N062Q-S103N-N117F-A194F、N062Q-S103N-V121F-S144R-H249R、N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N076D-S101G-S103A-V104I-A232V-Q245R、N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N076D-S103A-V104I-Q109R、N076D-S103A-V104I-Q109R-Q245R、N076D-S103A-V104I-S212P-E271V、N076D-S103A-V104I-S212P-Q245L-E271V、N076D-S87R-S103A-V104I-S212P-E271V、N117F-A194F-T213A-A270C、N117F-T213A-A215F、P052N-S078R-S103N-L148I-T213A、P052N-S103N-N116A-L148I-Y192W、R019H-G020R-T022W-S078R-S101G-S103A-V104I-G211Q-A232V-Q245R、R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、R045T-S078R-S101G-S103A-V104I-A232V-Q245R、R045T-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、S009A-G020R-N043R-S212F、S009A-G020R-N043R-W241R、S009A-G020R-S024R-N043R、S009A-N043R-S078R、S009A-N043R-S078R-S242R、S009A-N043R-S212F、S009A-N043R-W241R、S009A-T022R-N043R-S078R、S009A-T022R-S078R-S212F、S009A-T022R-S078R-S212F-W241R、S009A-T022R-S212F-W241R、S024R-A215F-N269R、S024R-A232V-Q245R、S024R-G025R-N183D-Y192W-P239S、S024R-N043A-N117F-A194F-G211Q、S024R-N043D-H249R、S024R-N043D-S101G-S103A-V104I-A232V-Q245R-H249R、S024R-N043D-S101G-S103A-V104I-A232V-Q245R-N269R、S024R-N043R-A215F、S024R-N043R-A230E、S024R-N043R-A230E-S242R、S024R-N043R-H249R、S024R-N043R-N076D-H249R、S024R-N043R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、S024R-N043R-N076D-S101G-S103A-V104I-A232V-Q245R、S024R-N043R-N116A-A215F、S024R-N043R-N116A-A215F-N269R、S024R-N043R-N116A-N269R、S024R-N043R-N116A-T213A-N269R、S024R-N043R-R045T-N076D-A230E-H249R、S024R-N043R-R045T-N269R、S024R-N043R-R045T-S101A-N116A-A215F-N269R、S024R-N043R-R045T-S101A-N116A-T213A-N269R、S024R-N043R-R045T-S242R、S024R-N043R-R045T-T213A-A215F-N269R、S024R-N043R-S101A-A215F、S024R-N043R-S101A-A215F-N269R、S024R-N043R-S101A-N116A、S024R-N043R-S101A-N116A-A215F-N269R、S024R-N043R-S101G-S103A-V104I-A232V-Q245R、S024R-N043R-S242R、S024R-N062Q-V104L-S106G-H249R、S024R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、S024R-N076D-V104I-A232V-Q245R、S024R-N116A-T213A-N269R、S024R-R045T、S024R-R045T-N076D-A230E-S242R-H249R、S024R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、S024R-R045T-S101G-S103A-V104I-A232V-Q245R-N269R、S024R-S078R-S212F、S024R-S078R-V104L-N116A-N183D、S024R-S087D-S101G-S103A-V104I-A232V-Q245R、S024R-S101A-H120F-A194F-H249R、S024R-S101A-N269R、S024R-S101G-S103A-V104I-A232V-Q245R、S024R-S101G-S103A-V104I-V150L-A232V-Q245R、S024R-S101G-V104I-Q245R、S024R-S103A-Q245R、S024R-S103A-V104I-A232V-H249R、S024R-S103A-V104I-H249R、S024R-S103A-V104I-Q245R、S024R-Y167W-T224A-H249R、S078R-S087D-S101G-S103A-V104I-A232V-Q245R、S078R-S101G-S103A-V104I-A232V-Q245R、S078R-S101G-S103A-V104I-A232V-Q245R-N269R、S078R-S101G-S103A-V104I-V150L-A232V-Q245R、S078R-S103N-S106G-Y167W-Q236N、S078R-V104L-T213A-A215F-T224A、S078R-Y091F-V121F-L233C-N252R、S087D-S101G-S103A-V104I-A232V-Q245R-N269R、S087R-S101G-S103A-V104I-Q109R-S212P-A232V-Q245R-E271V、S099F-S144R-Y167W-N252R、S101A-H120F-Y192W-A215F-T224A、S101A-S103A-V104I-T213A-A232V-Q245R-N269R、S101G-S103A-V104I-A232V-Q245R、S101G-S103A-V104I-A232V-Q245R-E271L、S101G-S103A-V104I-A232V-Q245R-H249R、S101G-S103A-V104I-A232V-Q245R-N269R、S101G-S103A-V104I-A232V-Q245R-N269R、S101G-S103A-V104I-A232V-S242R-Q245R、S101G-S103A-V104I-A232V-V244R-Q245R、S101G-S103A-V104I-G115R-A232V-Q245R、S101G-S103A-V104I-N116A-T213A-A232V-Q245R-N269R、S101G-S103A-V104I-Q109R-A232V-Q245R、S101G-S103A-V104I-Q109R-S212P-A232V-Q245R、S101G-S103A-V104I-Q109R-S212P-A232V-Q245R-E271V、S101G-S103A-V104I-S212F-A232V-Q245R、S101G-S103A-V104I-V150L-A232V-Q245R-H249R、S101G-S103A-V104I-V150L-A232V-Q245R-N269R、S105T-S128N-S144R-L148I-S212M、S106G-N117F-N238L、S144R-G211Q-N238L-P239S-H249R、T022R-N043R-S101G-S103A-V104I-A232V-Q245R、T022R-N076D-S101G-S103A-V104I-A232V-Q245R、T022R-S087D-S101G-S103A-V104I-A232V-Q245R、T022R-S101G-S103A-V104I-A232V-Q245R、T022W-S078R-Y167W-S212M-A270C、T057R-E089I-I198L、T057R-S099F-S105T-I198L-T213A、T057R-S099F-V121F-N185I-Y192W、T057R-Y167W-H249R、V004R-G020R-H249R、V004R-G020R-N043R、V004R-G020R-S024R、V004R-G020R-S024R-H249R、V004R-G020R-S024R-N043R、V004R-G020R-S024R-N043R-S242R、V004R-G020R-S024R-V244R、V004R-N043R-S101G-S103A-V104I-A232V-Q245R、V0
04R-S009A-G020R-N043R、V004R-S009A-G020R-N043R-S242R、V004R-S009A-G020R-S024R-S242R、V004R-S009A-G020R-S242R、V004R-S009A-N043R-W241R、V004R-S009A-S024R-N043R-W241R、V004R-S009A-S078R-W241R、V004R-S009A-W241R、V004R-S101G-S103A-V104I-A232V-Q245R、V104L-L217E-T224A-H249R-N252R、V104L-T213A-S216F、V121F-N252R-A270C、及び/又はY091F-S099F-S101A-S105T-Y167W;
e)S101G-S103A-V104I-A232V-Q236H-Q245R-N252K、S101G-S103A-V104I-A232V-Q245R-N248R、S101G-S103A-V104I-G159R-A232V-Q245R-N248D、A232V-Q245R、E089I-N117F-N185I-A215F-L233C、G020R-E089I-L217E、G020R-G023A-V104L-Y192W-L233C、G020R-N043D-R045T-N076D-S242R-H249R、G020R-N043D-R045T-S078R-S101G-S103A-V104I-A232V-Q245R、G020R-N043D-S101G-S103A-V104I-A232V-Q245R-H249R、G020R-N043R-N076D-A230E-H249R、G020R-N043R-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、G020R-N116A-A215F-N269R、G020R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、G020R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、G020R-R045T-N116A-N269R、G020R-R045T-S101G-S103A-V104I-A232V-Q245R、G020R-S024R-A215F、G020R-S024R-K27R-N043D-S242R-H249R、G020R-S024R-N043D-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、G020R-S024R-N043R-N076D、G020R-S024R-N043R-R045T-A215F、G020R-S024R-N043R-R045T-N076D-S242R-H249R、G020R-S024R-N043R-R045T-N116A-T213A-A215F、G020R-S024R-N076D-S101G-S103A-V104I-A232V-Q245R、G020R-S024R-T38I-N043R-R045T-N076D-S242R-H249R、G020R-S078R-S101A-S103A-V104I-A232V-Q245R、G020R-S078R-S101A-S103A-V104I-G211Q-T213A-A232V-Q245R、G020R-S078R-S101A-S103A-V104I-N116A-N183D-A232V-Q245R、G020R-S078R-S101A-S103A-V104I-N116A-N183D-G211Q-A232V-Q245R、G020R-S078R-S101A-S103A-V104I-N116A-N183D-G211Q-T213A-A215F-A232V-Q245R、G020R-S078R-S101A-S103A-V104I-N116A-N183D-G211Q-T213A-A232V-Q245R、G020R-S078R-S101A-S103A-V104I-N116A-N183D-I198L-A215F-A232V-Q245R、G020R-S078R-S101A-S103A-V104I-N183D-A215F-A232V-Q245R、G020R-S078R-S101G-S103A-V104I-N116A-A131V-N183D-T213A-A232V-Q245R、G020R-S078R-S101G-S103A-V104I-N116A-N183D-G211Q-T213A-A215F-A232V、G020R-S078R-S101G-S103A-V104I-N116A-N183D-G211Q-T213A-A215F-A232V-Q245R、G020R-S078R-S101G-S103A-V104I-N116A-N183D-T213A-A232V-Q245R、G020R-S078R-S101G-S103A-V104I-N183D-G211Q-T213A-A232V-Q245R-E271G、G020R-S078R-S101G-S103A-V104I-T180A-A232V-Q245R、G020R-S101A-S103A-V104I-N116A-N183D-G211Q-T213A-A215F-A232V-Q245R、G020R-S101A-S103A-V104I-N116A-N183D-T213A-A232V-Q245R、G020R-S101A-S103A-V104I-T213A-A215F-A232V-Q245R、G020R-S101A-S103G-V104V-A232V-Q245R、G020R-S101G-S103A-V104I-N116A-A232V-Q245R、G020R-S101G-S103A-V104I-N116A-G211Q-A232V-Q245R、G020R-S101G-S103A-V104I-N183D-G211Q-A232V-Q245R-、G020R-S103A-V104I-A232V-Q245R、G020R-S242R-H249R、G020R-T022W-S078R-S101A-S103A-V104I-A232V-Q245R、G020R-T022W-S078R-S101A-S103A-V104I-I198L-A232V-Q245R、G020R-T022W-S078R-S101A-S103A-V104I-N116A-N183D-G211Q-T213A-A215F-A232V-Q245R、G020R-T022W-S078R-S101A-S103A-V104I-N116A-N183D-T213A-A215F-A232V-Q245R、G020R-T022W-S078R-S101A-S103A-V104I-N183D-I198L-T213A-A215F-A232V-Q245R、G020R-T022W-S078R-S101G-S103A-V104I-G211Q-T213A-A232V-Q245R、G020R-T022W-S078R-S101G-S103A-V104I-N116A-N183D-A215F-A232V-Q245R、G020R-T022W-S101A-N116A-I198L-G211Q-T213A-A215F-H249R、G020R-T022W-S101A-S103A-V104I-A215F-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-G211Q-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-G211Q-T213A-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-I198L-G211Q-A215F-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-N116A-G211Q-A215F-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-N116A-G211Q-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-N116A-G211Q-T213A-A215F-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-G211Q-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-G211Q-T213A-A232V-Q245R、G020R-T022W-S101G-S103A-V104I-A114T-T213A-A215F-A232V-Q245R、G020R-T022W-S101G-S103A-V104I-G211Q-T213A-A215F-A232V-Q245R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-A215F-A232V-Q245R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-G211Q-A215F-A232V-Q245R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-I198L-A232V-Q245R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-T213A-A215F-A232V-Q245R、G020R-T022W-S101G-S103A-V104I-N183D-I198L-T213A-A215F-A232V-Q245R、G020R-T022W-S103A-G211Q-T213A-A215F-A232V-Q245R、G020R-T022W-S103A-V104I-A232V-Q245R、G020R-T22W-S078R-S101A-S103A-V104I-N116A-N183D-A215F-A232V-Q245R、G020R-T22W-S078R-S101A-S103A-V104I-N116A-N183D-T213A-A232V-Q245R、G020R-T22W-S101A-S103A-V104I-G211Q-A215F-A232V-Q245R、G020R-T22W-S101A-S103A-V104I-N116A-G211Q-A215F-A232V-Q245R、G020R-T22W-S101A-S103A-V104I-N116A-G211Q-T213A-A215F-A232V-Q245R、G020R-T22W-S101G-S103A-V104I-N116A-N183D-A215F-A232V-Q245R、G020R-T22W-S101G-S103A-V104I-N116A-N183D-T213A-A215F-A232V-Q245R、G025R-N043A-Y091F-I198L-A270C、G025R-S105T-S128N-S144R-A270C、G046R-E089I-S099F-R186K-S212M、G118R-A172V、G118R-A194T、G118R-Y209A-K235F、H017Y-S024R-T033S-P086W、I008T-S024R、K027R-N043R-S101G-S103A-V104I-A232V-Q245R-N269R、K027R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、K235F-N243F、N018R-G020R-H249R、N018R-G020R-N043D-H249R、N018R-G020R-N043D-R045T-A230E-S242R、N018R-G020R-N043D-R045T-N076D-S242R、N018R-G020R-N043D-R045T-S240P、N018R-G020R-N043D-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-N043D-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-N043R、N018R-G020R-N043R-N076D、N018R-G020R-N043R-N076D-A230E-S242R、N018R-G020R-N043R-R045T-N076D-H249R、N018R-G020R-N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-G020R-R045T-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-S024R-N043D-N0
76D-S242R、N018R-G020R-S024R-N043D-R045T-S242R、N018R-G020R-S024R-N043R-N076D-H249R、N018R-G020R-S024R-N043R-R045T-N076D-H249R、N018R-G020R-S024R-N076D-A215F-H249R、N018R-G020R-S024R-N076D-G211Q-A215F-H249R、N018R-G020R-S024R-N076D-L217E-H249R、N018R-G020R-S024R-N076D-N116A-A215F-H249R、N018R-G020R-S024R-N076D-N116A-N183D-A215F-H249R、N018R-G020R-S024R-N076D-N116A-N183D-I198L-G211Q-H249R、N018R-G020R-S024R-N076D-N116A-N183D-T213A-A215F-H249R、N018R-G020R-S024R-N076D-N183D-H249R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-I198L-H249R、N018R-G020R-S024R-N076D-S101A-N183D-G211Q-A215F-H249R、N018R-G020R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-I198L-T213A-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-N183D-H249R、N018R-G020R-T22W-S024R-N076D-N116A-N183D-I198L-T213A-H249R、N018R-N043D-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-N043D-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-N043D-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-N043D-R045T-N076D-S242R-H249R、N018R-N043D-R045T-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-N043D-R045T-S101G-S103A-V104I-A232V-Q245R、N018R-N043D-R045T-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-N043D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-N043R-N076D-A230E-S242R-H249R、N018R-N043R-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-N043R-N076D-S242R-H249R、N018R-N043R-R045T-N076D-A230E-S242R、N018R-N043R-R045T-N076D-S076T-S101G-S103A-V104I-A232V-Q245R-A273T、N018R-N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-N043R-R045T-N076D-S242R、N018R-N043R-R045T-S242R、N018R-N076D-H249R、N018R-N076D-Q245R、N018R-N076D-S101G-A232V-Q245R、N018R-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-N076D-S101G-S103A-V104I-H249R、N018R-N076D-S101G-V104I-H249R、N018R-N076D-S103A-V104I-H249R、N018R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-S024R-N043D-A230E-H249R、N018R-S024R-N043D-A230E-S242R、N018R-S024R-N043D-H249R、N018R-S024R-N043D-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-S024R-N043D-N076D-S242R-H249R、N018R-S024R-N043D-N076D-V150L-H249R、N018R-S024R-N043D-S242R、N018R-S024R-N043D-S242R-H249R、N018R-S024R-N043R-N076D-L217E-H249R、N018R-S024R-N043R-N076D-S078R-H249R、N018R-S024R-N043R-R045T-A230E-H249R、N018R-S024R-N076D、N018R-S024R-N076D-A232V-H249R、N018R-S024R-N076D-G211Q-H249R、N018R-S024R-N076D-I198L-G211Q-A215F-H249R、N018R-S024R-N076D-I198L-G211Q-T213A-H249R、N018R-S024R-N076D-I198L-T213A-A215F-H249R、N018R-S024R-N076D-I198M-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-L088I-S101A-N116A-I198L-G211Q-A215F-H249R、N018R-S024R-N076D-N116A-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-N116A-H249R、N018R-S024R-N076D-N116A-I198L-A215F-H249R、N018R-S024R-N076D-N116A-I198L-A215F-H249R-V268G、N018R-S024R-N076D-N116A-I198L-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-N116A-I198L-G211Q-T213A-H249R、N018R-S024R-N076D-N116A-I198L-H249R、N018R-S024R-N076D-N116A-I198L-T213A-H249R、N018R-S024R-N076D-N116A-I198L-Y209H-T213A-H249R、N018R-S024R-N076D-N116A-M117I-N183D-T213A-H249R、N018R-S024R-N076D-N116A-N183D-G211Q-H249R、N018R-S024R-N076D-N116A-T213A-H249R、N018R-S024R-N076D-N183D-I198L-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-N183D-T213A-A215F-H249R、N018R-S024R-N076D-S101A-G211Q-A215F-H249R、N018R-S024R-N076D-S101A-G211Q-H249R、N018R-S024R-N076D-S101A-H249R、N018R-S024R-N076D-S101A-I198L-A215F-H249R、N018R-S024R-N076D-S101A-I198L-G211Q-H249R、N018R-S024R-N076D-S101A-I198L-H249R、N018R-S024R-N076D-S101A-I198L-T213A-H249R、N018R-S024R-N076D-S101A-N116A-G211Q-T213A-H249R、N018R-S024R-N076D-S101A-N116A-I198L-G211Q-H249R、N018R-S024R-N076D-S101A-N116A-I198L-G211Q-T213A-H249R、N018R-S024R-N076D-S101A-N116A-I198L-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N116A-N183D-I198L-T213A-H249R、N018R-S024R-N076D-S101A-N116A-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N183D-G211Q-H249R、N018R-S024R-N076D-S101A-N183D-T213A-H249R、N018R-S024R-N076D-S101G-A232V、N018R-S024R-N076D-S103A-A232V-Q245R、N018R-S024R-N076D-T213A-H249R、N018R-S024R-N076D-V104I、N018R-S024R-Q245R、N018R-S024R-R045T-A230E-S242R、N018R-S024R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-S024R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-S024R-S242R、N018R-S024R-V104I、N018R-S024R-V30S-L31S-D32I-T33Q-G34V-I35F、N018R-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、N018R-S101G-S103A-V104I、N018R-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-S101G-V104I、N018R-S103A、N018R-S103A-V104I-A232V、N018R-T022K-N043D-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-G211Q-H249R、N018R-T022W-S024R-N076D-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-I198L-A215F-H249R、N018R-T022W-S024R-N076D-I198L-G211Q-H249R、N018R-T022W-S024R-N076D-I198L-T213A-A215F-H249R、N018R-T022W-S024R-N076D-N116A-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-N116A-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-N116A-I198L-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-N116A-I198L-T213A-H249R、N018R-T022W-S024R-N076D-N116A-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-G211Q-H249R、N018R-T022W-S024R-N076D-S101A-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-S101A-I198L-G211Q-Q245R、N018R-T022W-S024R-N076D-S101A-I198L-
G211Q-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-I198L-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-G211Q-H249R、N018R-T022W-S024R-N076D-S101A-N116A-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N116A-I198L-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-I198L-G211Q-H249R、N018R-T022W-S024R-N076D-S101A-N116A-I198L-G211Q-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-I198L-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N116A-I198L-H249R、N018R-T022W-S024R-N076D-S101A-N116A-I198L-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-I198L-T213A-H249R、N018R-T022W-S024R-N076D-S101A-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-T213A-H249R、N018R-T022W-S024R-N076D-T213A-A215F-H249R、N018R-T22W-S024R-N076D-I198L-A215F-H249R、N018R-T22W-S024R-N076D-N116A-G211Q-H249R、N018R-T22W-S024R-N076D-N116A-G211Q-T213A-H249R、N018R-T22W-S024R-N076D-N116A-T213A-A215F-H249R、N018R-T22W-S024R-N076D-S101A-A215F-H249R、N018R-T22W-S024R-N076D-S101A-G211Q-T213A-H249R、N018R-T22W-S024R-N076D-S101A-I198L-A215F-H249R、N018R-T22W-S024R-N076D-S101A-I198L-T213A-A215F-H249R、N018R-T22W-S024R-N076D-S101A-N116A-A215F-H249R、N018R-T22W-S024R-N076D-S101A-N116A-I198L-A215F-H249R、N018R-T22W-S024R-N076D-T213A-A215F-H249R、N018R-V104I、N043D-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N043D-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N043D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R-A272V、N043D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R-R275S、N043D-S101G-S103A-V104I-A232V-Q245R、N043D-S101G-S103A-V104I-A232V-Q245R-H249R、N043R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N043R-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、N043R-N076D-S101G-S103A-V104I-L217E-A232V-Q245R、N043R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N043R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-V234I-Q245R、N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N043R-R045T-S078R-S101G-S103A-V104I-N218S-A232V-Q245R、N043R-R045T-S101G-S103A-V104I-A232V-Q245R、N043R-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N043R-S087D-S101G-S103A-V104I-A232V-Q245R、N062Q-S101A-Q236N-N252R-A270C、N076D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N076D-S101G-S103A-V104I-A232V-Q245R-H249R、N076D-S101G-S103A-V104I-A232V-S242R-Q245R、P005S-S024R-T033S-N243F、P014L-G020R-S024R-N043R-R045T-S101A-A215F、P052N-V104L-N183D-S216F-H249R、P086W-G118R、P086W-N243F、P086W-Y209A、Q012H-G020R-S078R-S101G-S103A-V104I-I198L-G211Q-T213A-A232V-Q245R、R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、R045T-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、R045T-S101G-S103A-V104I-A232V-Q245R-N269R、R045T-S242R-H249R、S024C-T033S、S024R-A232V、S024R-G046R-Y091F-V121F、S024R-G118R-K235F、S024R-N043A-S105T-S106G-I198L、S024R-N043D-R045T-S242R-H249R、S024R-N043D-S101G-S103A-V104I-A232V-Q245R、S024R-N043D-S242R-H249R、S024R-N043R-N076D、S024R-N043R-N076D-A230E-S242R、S024R-N043R-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、S024R-N043R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、S024R-N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、S024R-N043R-R045T-S242R-H249R、S024R-N043R-S101A-T213A、S024R-N076D-Q245R、S024R-N076D-S101G-A232V-Q245R、S024R-N076D-S101G-M175L-A232V-Q245R、S024R-N076D-S101G-Q245R、S024R-N076D-S101G-S103A-V104I-A232V-Q245R、S024R-N076D-S103A-V104I-Q245R、S024R-N076D-V104I-Q245R、S024R-N243F、S024R-P086R-G118R、S024R-P086W-Y209A-K235F、S024R-P239Q、S024R-Q245R-H249R、S024R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、S024R-S101G、S024R-S101G-Q245R、S024R-S101G-V104I-H249R、S024R-S103A-A232V、S024R-S103A-M175L-A232V-H249R、S024R-S141G、S024R-T033S、S024R-T033S-A194T、S024R-T033S-G118R-K235F、S024R-T033S-G118R-Y209A、S024R-T033S-K235F、S024R-T033S-S078R-G118R、S024R-T033S-S078R-N243F、S024R-T033S-Y209A、S024R-T033S-Y209A-N243F、S024R-T274I、S024R-V104I-H249R、S024R-V104I-Q245R、S024R-Y091F-I198L-A215F-P239S、S024R-Y209A、S024R-Y209A-K235F、S024R-Y209A-S242P、S078R-P086W、S078R-S099F-N116A-R186K-T224A、S078R-S101G-S103A-V104I-A232V-Q245R-H249R、S101G-A232V、S101G-S103A-V104I-A232V-H249R、S101G-S103A-V104I-A232V-Q245R-H249R-N269R、S101G-S103A-V104I-Q245R、S105T-G211Q-S216F、S106G-N185I-S216F-Q236N、T022R-S101G-S103A-V104I-V150L-A232V-Q245R、T033S-G118D-A138V-Y209A、T033S-G118R-Y209A-、T033S-L148F、T033S-N243F、T033S-P086W、T033S-P201S、T033S-S078R、T033S-W241R、T033S-Y209A、T033S-Y209A-K235F、V004M-N018R-S024R-N076D-N116A-I198L-G211Q-T213A-H249R、V104I-A232V-H249R、及び/又はV104L-H120F-R186K-S216F-N252R;
f)A015T-T033S、A016T-N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、A230E-H249R、A232V-H249R、E089I-S105T-N116A-A215F-S216F、E089I-Y091F-N185I-G211Q-A270C、G020R-A090S-S101G-S103A-V104I-N116A-N183D-T213A-A215F-A232V-Q245R、G020R-N043D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、G020R-N043R-N076D、G020R-N043R-R045T-S078R-S101G-S103A-V104I-A232V-Q245R、G020R-P052N-S101A-I198L-L233C、G020R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、G020R-S024R-N043D-N076D-H249R、G020R-S024R-N043D-N076D-S242R-H249R、G020R-S024R-N043D-R045T-A230E-S242R、G020R-S024R-N043D-S078R-S101G-S103A-V104I-A232V-Q245R、G020R-S024R-N043D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、G020R-S024R-N043R-S101G-S103A-V104I-A232V-Q245R、G020R-S024R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、G020R-S024R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、G020R-S024R-R045T-N076D-S242R-H249R、G020R-S024R-R045T-S101G-S103A-V104I-A232V-Q245R、G020R-S078R-S101A-S103A-V104I-G115E-N116A-N183D-G211Q-T213A-A232V-Q245R、G020R-S101A-S103A-V104I-N116A-N183D-A215F-A232V-Q245R、G020R-S101A-S103A-V104I-N116A-N183D-A232V-Q245R、G020R-S101A-S103A-V104I-N116A-N183D-G211Q-A232V-Q245R、G020R-S101A-S103A-V104I-N116A-N183D-G211Q-A232V-Q245R-T274I、G020R-S101A-S103A-V104I-N116A-N183D-I198L-G211Q-T213A-A215F-A232V-Q245R、G020R-S101A-S103A-V104I-N116A-N183D-T213A-A215F-A232V-Q245R、G020R-S101A-S103A-V104I-T213A-A232V-Q245R、G020R-S101G-S103A-V104I-N116A-N183D-A232V-Q245R、G020R-S101G-S103A-V104I-N116A-N183D-G211Q-A215F-A232V-Q245R、G020R-S101G-S103A-V104I-N116A-N183D-G211Q-A232V-Q245R、G020R-S101G-S103A-V104I-N116A-N183D-G211Q-T213A-A215F-A232V-Q245R、G020R-S101G-S103A-V104I-N116A-N183D-G211Q-T213A-A232V-Q245R、G020R-S101G-S103A-V104I-N116A-N183D-T213A-A232V-Q245R、G020R-T022R-N269R、G020R-T022R-S078R-S212F-W241R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-A215F-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-A232V-Q245R-N269S、G020R-T022W-S101A-S103A-V104I-N116A-N183D-A232V-Q245R-T274I、G020R-T022W-S101A-S103A-V104I-N116A-N183D-G211Q-A215F-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-I198L-G211Q-T213A-A215F-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-T213A-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-N183D-G211Q-T213A-A215F-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-N183D-I198L-A215F-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-N183D-T213A-A215F-A232V-Q245R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-A232V-Q245R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-G211Q-A232V-Q245R-N263S、G020R-T022W-S101G-S103A-V104I-N116A-N183D-G211Q-T213A-A215F-A232V-Q245R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-G211Q-T213A-A232V-Q245R、G020R-T022W-S101G-S103A-V104I-N183D-A215F-A232V-Q245R、G020R-T022W-S101G-S103A-V104I-N183D-A232V-Q245R、G025R-N062Q-S128N-S144R-N185I、G025R-N116A-H120F-T224A-A270C、G118R-K235F、K027R-N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N018K-N076D-S078R-S101G-S103A-V104I-L217E-A232V-Q245R-N269R、N018R-G020R-N043D-N076D-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、N018R-G020R-N043D-N076D-S242R-H249R、N018R-G020R-N043D-R045T-N076D-H249R、N018R-G020R-N043D-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-N043D-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-G020R-N043D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-G020R-N043D-S101G-S103A-V104I-L217E-A232V-Q245R、N018R-G020R-N043R-R045T-H249R、N018R-G020R-N043R-R045T-N076D-A230E-H249R、N018R-G020R-N076D、N018R-G020R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-G020R-R045T-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-G020R-S024R-N043D-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-S024R-N043D-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-G020R-S024R-N043R-N076D、N018R-G020R-S024R-N076D-A131T-A215F-H249R、N018R-G020R-S024R-N076D-G211Q-H249R、N018R-G020R-S024R-N076D-G211Q-N243D-H249R、N018R-G020R-S024R-N076D-G211Q-T213A-A215F-H249R、N018R-G020R-S024R-N076D-G211Q-T213A-H249R、N018R-G020R-S024R-N076D-I198L-A215F-H249R、N018R-G020R-S024R-N076D-I198L-H249R、N018R-G020R-S024R-N076D-I198L-T213A-A215F-H249R、N018R-G020R-S024R-N076D-N116A-G211Q-T213A-A215F-H249R、N018R-G020R-S024R-N076D-N116A-H249R、N018R-G020R-S024R-N076D-N116A-I198L-G211Q-A215F-H249R-N269S、N018R-G020R-S024R-N076D-N116A-I198L-G211Q-A215F-Q245R、N018R-G020R-S024R-N076D-N116A-I198L-H249R、N018R-G020R-S024R-N076D-N116A-N183D-G211Q-A215F-H249R、N018R-G020R-S024R-N076D-N116A-N183D-G211Q-T213A-H249R、N018R-G020R-S024R-N076D-N116A-N183D-I198L-A215F-H249R、N018R-G020R-S024R-N076D-N116A-N183D-I198L-G211Q-A215F-H249R、N018R-G020R-S024R-N076D-N116A-N183D-I198L-G211Q-T213A-H249R、N018R-G020R-S024R-N076D-N116A-N183D-I198L-H249R、N018R-G020R-S024R-N076D-N116A-N183D-T213A-H249R、N018R-G020R-S024R-N076D-N183D-A215F-H249R、N018R-G020R-S024R-N076D-N183D-G211Q-H249R、N018R-G020R-S024R-N076D-N183D-G211Q-T213A-A215F-H249R、N018R-G020R-S024R-N076D-N183D-G211Q-T213A-H249R、N018R-G020R-S024R-N076D-N183D-I198L-A215F-H249R、N018R-G020R-S024R-N076D-N183D-I198L-G211Q-A215F-H249R、N018R-G020R-S024R-N076D-N204D-T213A-H249R、N018R-G020R-S024R-N076D-S101A-G211Q-A215F-H249R-N269D、N018R-G020R-S024R-N076D-S101A-H249R、N018R-G020R-S024R-N076D-S101A-I198L-T213A-A215F-H249R、N018R-G020R-S024R-
N076D-S101A-N116A-G211Q-T213A-A215F-H249R、N018R-G020R-S024R-N076D-S101A-N116A-G211Q-T213A-H249R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-G211Q-A215F-H249R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-G211Q-T213A-H249R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-H249R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-A215F-H249R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-I198L-T213A-H249R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-T213A-H249R、N018R-G020R-S024R-N076D-S101A-N116A-T213A-A215F-H249R、N018R-G020R-S024R-N076D-S101A-N116A-T213A-H249R、N018R-G020R-S024R-N076D-S101A-N183D-G211Q-H249R、N018R-G020R-S024R-N076D-S101A-N183D-I198L-A215F-H249R、N018R-G020R-S024R-N076D-S101A-N183D-I198L-G211Q-T213A-H249R、N018R-G020R-S024R-N076D-S101A-N183D-I198L-T213A-H249R、N018R-G020R-S024R-N076D-S101A-N183D-T213A-A215F-H249R、N018R-G020R-S024R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-S024R-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-I198L-T213A-H249R、N018R-G020R-T022W-S024R-N076D-N116A-I198L-H249R、N018R-G020R-T022W-S024R-N076D-N116A-I198L-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-G211Q-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-I198L-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-T213A-H249R、N018R-G020R-T022W-S024R-N076D-N183D-G211Q-T213A-H249R、N018R-G020R-T022W-S024R-N076D-N183D-I198L-G211Q-H249R、N018R-G020R-T022W-S024R-N076D-S101A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-G211Q-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-G211Q-T213A-H249R、N018R-G020R-T022W-S024R-N076D-S101A-I198L-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-I198L-G211Q-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-G211Q-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-I198L-G211Q-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-I198L-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-N183D-G211Q-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-N183D-G211Q-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-T213A-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-N183D-T213A-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-T213A-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N183D-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N183D-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-T213A-H249R、N018R-N043D-A230E-H249R、N018R-N043D-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-N043D-N076D-S242R-H249R、N018R-N043D-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-N043D-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-N043D-R045T-S078R-S101G-S103A-V104I-A232V-Q245R-A272D、N018R-N043R-N076D-A230E-H249R、N018R-N043R-N076D-S242R、N018R-N043R-R045T-A230E-S242R、N018R-N043R-R045T-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、N018R-N043R-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-N043R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-N076D-A232V-H249R、N018R-N076D-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、N018R-N076D-S101G-I198T-A232V、N018R-N076D-S101G-S103A-V104I-Q245R、N018R-N076D-S101G-V104I、N018R-N076D-S242R、N018R-N076D-S242R-H249R、N018R-N076D-V104I-Q245R-H249R、N018R-R045T-H249R、N018R-R045T-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-R045T-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-S024R-N043D-N076D-S087D-H249R、N018R-S024R-N043D-N076D-S242R、N018R-S024R-N076D-A086V-S101A-N183D-I198L-G211Q-H249R、N018R-S024R-N076D-A215F-H249R、N018R-S024R-N076D-A232V、N018R-S024R-N076D-I198L-A215F-H249R、N018R-S024R-N076D-I198L-G211Q-H249R、N018R-S024R-N076D-I198L-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-I198L-H249R、N018R-S024R-N076D-I198L-T213A-H249R、N018R-S024R-N076D-L217E-H249R-N269R、N018R-S024R-N076D-N116A-A150T-T213A-H249R、N018R-S024R-N076D-N116A-G211Q-T213A-H249R、N018R-S024R-N076D-N116A-I198L-G211Q-H249R、N018R-S024R-N076D-N116A-I198L-T213A-A215F-H249R、N018R-S024R-N076D-N116A-N183D-A215F-H249R、N018R-S024R-N076D-N116A-N183D-G211Q-A215F-H249R、N018R-S024R-N076D-N116A-N183D-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-N116A-N183D-G211Q-T213A-H249R、N018R-S024R-N076D-N116A-N183D-H249R、N018R-S024R-N076D-N116A-N183D-I198L-A215F-H249R、N018R-S024R-N076D-N116A-N183D-I198L-G211Q-A215F-H249R、N018R-S024R-N076D-N116A-N183D-I198L-G211Q-H249R、N018R-S024R-N076D-N116A-N183D-I198L-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-N116A-N183D-I198L-G211Q-T213A-H249R、N018R-S024R-N076D-N116A-N183D-I198L-H249R、N018R-S024R-N076D-N116A-N183D-I198L-T213A-H249R、N018R-S024R-N076D-N116A-N183D-T213A-A215F-H249R、N018R-S024R-N076D-N116A-N183D-T213A-H249R、N018R-S024R-N076D-N183D-A215F-H249R、N018R-S024R-N076D-N183D-G211Q-H249R、N018R-S024R-N076D-N183D-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-N183D-G211Q-T213A-H249R、N018R-S024R-N076D-N183D-H249R、N018R-S024R-N076D-N183D-H249R-A248T、N018R-S024R-N076D-N183D-I198L-A215F-H249R、N018R-S024R-N076D-N183D-I198L-G211Q-A215F-H249R、N018R-S024R-N076D-N183D-I198L-G211Q-H249R、N018R-S024R-N076D-N183D-I198L-H249R、N018R-S024R-N076D-N183D-I198L-T213A-A21
5F-H249R、N018R-S024R-N076D-N183D-I198L-T213A-H249R、N018R-S024R-N076D-N183D-T213A-H249R、N018R-S024R-N076D-S087D-H249R、N018R-S024R-N076D-S101A-G211Q-T213A-A215F-H249R-A270V、N018R-S024R-N076D-S101A-G211Q-T213A-H249R、N018R-S024R-N076D-S101A-I198L-G211Q-A215F-H249R、N018R-S024R-N076D-S101A-N116A-G211Q-A215F-H249R、N018R-S024R-N076D-S101A-N116A-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N116A-H249R、N018R-S024R-N076D-S101A-N116A-I198L-G211Q-A215F-H249R、N018R-S024R-N076D-S101A-N116A-I198L-H249R、N018R-S024R-N076D-S101A-N116A-I198L-T213A-H249R、N018R-S024R-N076D-S101A-N116A-N183D-A215F-H249R、N018R-S024R-N076D-S101A-N116A-N183D-G211Q-A215F-H249R、N018R-S024R-N076D-S101A-N116A-N183D-G211Q-H249R、N018R-S024R-N076D-S101A-N116A-N183D-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N116A-N183D-G211Q-T213A-H249R、N018R-S024R-N076D-S101A-N116A-N183D-H249R、N018R-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-T213A-H249R、N018R-S024R-N076D-S101A-N116A-N183D-I198L-H249R、N018R-S024R-N076D-S101A-N116A-N183D-I198L-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N116A-N183D-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N116A-N183D-T213A-H249R、N018R-S024R-N076D-S101A-N183D-A215F-H249R、N018R-S024R-N076D-S101A-N183D-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N183D-H249R、N018R-S024R-N076D-S101A-N183D-I198L-A215F-H249R、N018R-S024R-N076D-S101A-N183D-I198L-G211Q-H249R、N018R-S024R-N076D-S101A-N183D-I198L-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N183D-I198L-G211Q-T213A-H249R、N018R-S024R-N076D-S101A-N183D-I198L-H249R、N018R-S024R-N076D-S101A-N183D-I198L-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N183D-I198L-T213A-H249R、N018R-S024R-N076D-S101A-N183D-T213A-A215F-H249R、N018R-S024R-N076D-S101A-T213A-A215F-H249R、N018R-S024R-N076D-S101A-V197A-T213A-A215F-H249R、N018R-S024R-N076D-S101G、N018R-S024R-N076D-S101G-Q245R、N018R-S024R-N076D-S101G-S103A-V104I-A232V、N018R-S024R-N076D-S103A-H249R、N018R-S024R-N076D-S103A-V104I-L135I-A232V、N018R-S024R-N076D-T213A-A215F-H249R-T260K、N018R-S024R-N076D-V150L-S242R-H249R、N018R-S024R-R045T-A230E-H249R、N018R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-T022R-S024R-N076D-S101A-N116A-N183D-G211Q-H249R、N018R-T022W-S024R-N076D-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-I198L-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-I198L-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-I198L-H249R、N018R-T022W-S024R-N076D-I198L-T213A-H249R、N018R-T022W-S024R-N076D-N116A-A215F-H249R、N018R-T022W-S024R-N076D-N116A-G211Q-T213A-A215F-H249R、N018R-T022W-S024R-N076D-N116A-H249R、N018R-T022W-S024R-N076D-N116A-I198L-A215F-H249R、N018R-T022W-S024R-N076D-N116A-I198L-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-N116A-I198L-G211Q-T213A-A215F-H249R、N018R-T022W-S024R-N076D-N116A-I198L-H249R、N018R-T022W-S024R-N076D-N116A-I198L-T213A-A215F-H249R、N018R-T022W-S024R-N076D-N116A-N183D-A215F-H249R、N018R-T022W-S024R-N076D-N116A-N183D-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-N116A-N183D-G211Q-H249R、N018R-T022W-S024R-N076D-N116A-N183D-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-N116A-N183D-G211Q-T213A-Q245R、N018R-T022W-S024R-N076D-N116A-N183D-I198L-A215F-H249R、N018R-T022W-S024R-N076D-N116A-N183D-I198L-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-N116A-N183D-I198L-G211Q-H249R、N018R-T022W-S024R-N076D-N116A-N183D-I198L-G211Q-T213A-A209V-H249R、N018R-T022W-S024R-N076D-N116A-N183D-I198L-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-N116A-N183D-I198L-H249R、N018R-T022W-S024R-N076D-N116A-N183D-I198L-Y209H-G211Q-H249R、N018R-T022W-S024R-N076D-N116A-N183D-T213A-A215F-H249R、N018R-T022W-S024R-N076D-N116A-N183D-T213A-H249R、N018R-T022W-S024R-N076D-N183D-G211Q-H249R、N018R-T022W-S024R-N076D-N183D-G211Q-T213A-A215F-H249R、N018R-T022W-S024R-N076D-N183D-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-N183D-H249R、N018R-T022W-S024R-N076D-N183D-I198L-A215F-H249R、N018R-T022W-S024R-N076D-N183D-I198L-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-N183D-I198L-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-N183D-I198L-H249R、N018R-T022W-S024R-N076D-N183D-T213A-H249R、N018R-T022W-S024R-N076D-S101A-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-S101A-I198L-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-S101A-I198L-G211Q-H249R、N018R-T022W-S024R-N076D-S101A-I198L-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N116A-G211Q-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-G211Q-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-G211Q-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N116A-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-T213A-A215F-H249R-L267I、N018R-T022W-S024R-N076D-S101A-N116T-I198L-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N183D-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N183D-G211Q-H249R、N018R-T022W-
S024R-N076D-S101A-N183D-G211Q-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N183D-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N183D-I198L-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N183D-I198L-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N183D-I198L-Y209H-H249R、N018R-T022W-S024R-N076D-S101A-N183D-T213A-A215F-H249R、N018R-T22W-S024R-N076D-G211Q-T213A-H249R、N018R-T22W-S024R-N076D-N116A-I198L-T213A-H249R、N018R-T22W-S024R-N076D-S101A-I198L-H249R、N018R-V104I-A232V、N043A-Q059A-S101A-S216F-T224A、N043D-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、N043D-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N043D-R045T-S078R-S101G-S103A-V104I-A232V-Q245R、N043D-R045T-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N043D-S242R-H249R、N043R-A230E-H249R、N043R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N043R-N076D-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、N043R-N076D-S101G-S103T-V104I-A232V-Q245R-H249R-N269R、N043R-R045T-H249R、N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N043R-R045T-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N043R-R045T-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、N043R-R045T-S101G-S103A-V104I-A232V-Q245R-H249R、N043R-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、N043R-S101G-S103A-V104I-Q245R-H249R、N043R-S101G-S103A-V104I-V150L-A232V-Q245R-N269R、N076D-A232V-Q245R、N076D-Q245R、N076D-S101G-A232V-Q245R、N076D-S101G-S103A-Q245R、N076D-S101G-S103A-V104I-A232V-H249R、N076D-S101G-S103A-V104I-H249R、N076D-S101G-S103A-V104I-V150L-A232V-Q245R、N076D-S101G-V104I-H249R、N076D-S101G-V104I-Q245R、N076D-S103A-V104I-A232V-Q245R、N076D-S103A-V104I-Q245R、N076D-V104I-A232V-Q245R、N076D-V104I-Q245R、P005S-N018R-T022W-S024R-N076D-S101A-T213A-A215F-H249R、P086W-K235F、P086W-Y209A-K235F、Q012H-V104A-G118R、R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、R045T-S101G-S103A-V104I-A232V-Q245R、S024R-G118R-N243F-R269H、S024R-K235F-N243F、S024R-N043D-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、S024R-N043R-N076D-A230E-H249R、S024R-N076D-A232V-H249R、S024R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、S024R-N076D-S101G、S024R-N076D-S101G-A232V-H249R、S024R-N076D-S101G-S103A-A232V、S024R-N076D-S101G-S103A-V104I-M175L-H249R、S024R-N076D-S101G-S103A-V104I-Q245R、S024R-N076D-S101G-V104I-A232V-H249R、S024R-N076D-S103A-H249R、S024R-N076D-S103A-Q245R、S024R-N076D-S103A-V104I-H249R、S024R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、S024R-R045T-S242R-A273V、S024R-R247H、S024R-S101G-S103A、S024R-S101G-S103A-A232V、S024R-S101G-S103A-V104I、S024R-S103A-Q245R-H249R、S024R-S103A-V104I、S024R-S106G-N116A-S212M-T224A、S024R-T033S-A151V、S024R-T033S-A174V-K235F、S024R-T033S-A228T、S024R-T033S-K235F-W241R、S024R-T033S-N243F、S024R-V104A、S024R-V104I-A232V、S024R-Y209A-N243F、S078R-K235F、S087D-S101G-S103A-V104I-A232V-S242R-Q245R、S099F-S105T-S106G-A194F-S212M、S101G-H249R、S101G-S103A-V104I、S101G-S103A-V104I-A232V-Q245R-N248D、S101G-S103A-V104I-G159D-A232V-Q245R、S101G-S103A-V104I-G159D-A232V-Q245R-N248R、S101G-S103A-V104I-V150L-A232V-Q245R、S103A-A232V、S103A-A232V-H249R、S103A-A232V-Q245R、S103A-V104I-Q245R、S103N-H120F-Y167W-I198L-L233C、T022W-A194F-T213A-L233C-N238L、T022W-E089I-S216F、T033S-A048T、T033S-P086W-S156L-Y209A、T033S-P239T、T033S-T253A、T057R-N183D-Q236N、T143A-Y209A、V004E-T033S-S078R、V004R-S009A-T022R-S078R-S212F、及び/又はY209A-K235F;のうちの1つ以上を含み、任意選択で、次の変異:S103A、G159D、Q236H、Q245R、N248D及びN252Kのうちの1つ以上を含む、プロテアーゼ変異体を提供する。
A-S128N-A158E-R186H-E271F、S101A-S128N-A158E-Y209E-H249R、S101A-V104L-A158E-R186H-S188D-H249R、S101G-S103A-V104I-A158E-A232V-Q245R-N248D-H249R、S101G-S103A-V104I-A158E-G159E-A232V-Q245R-N248D-H249R、S101G-S103A-V104I-A158E-S188D-M222Q-A232V-Q245R-N248D-H249R、S101G-S103A-V104I-A158E-S188D-M222S-A232V-Q245R-N248D-H249R、S101G-S103A-V104I-A232V-M222Q-Q245R、S101G-S103A-V104I-P129E-A158E-S188D-A232V-Q245R-N248D-H249R、S101G-S103A-V104I-P129E-G159E-A232V-Q245R-N248D-H249R、S101G-S103A-V104I-P129E-S188D-A232V-N238R-Q245R-N248D、S101G-S103A-V104I-P129E-S188D-A232V-Q245R-N248D-H249R、S101G-S103A-V104I-S188D-A232V-Q245R-N248D-H249R、S101G-S103G-V104I-A158E-S188D-A232V-Q245R-N248D-H249R、S101G-S103S-V104I-A158E-S188D-A232V-Q245R-N248D-H249R、S101S-S103A-V104I-A158E-S188D-A232V-Q245R-N248D-H249R、S101S-S103G-V104I-A158E-S188D-A232V-Q245R-N248D-H249R、S101S-S103G-V104V-A158E-S188D-A232V-Q245R-N248D-H249R、S128N-A158E-G159E-E271F、S128N-A158E-H249R、S128N-A158E-R186H-E271F、S128N-A158E-R186H-H249R、S128N-A158E-R186H-S188D-E271F、S128N-A158E-S188D-E271F、S128N-A158E-S188D-H249R、S128N-A158E-S188D-Y209E-E271F、S128N-A158E-Y209E-、T022A-N043R-S103A-V104I-G118R-P129E-G159D-S188D-A232V-Q245R-N248D、T022A-N062E-A158E、T022A-S024R-S101D-S103A-V104I-G118R-G159D-S188D-A232V-N248D-E271F、T022A-S024R-S101D-S103A-V104I-G118R-P129E-G159D-S188D-A232V-Q245R-N248D、T022A-S024R-S101D-S103A-V104I-G159D-S188D-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-A158E-A232V-N238R-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-A158E-A232V-Q245R-N248D-H249R、T022A-S024R-S101G-S103A-V104I-A158E-G159E-S188D-A232V-N238R-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-A158E-G159E-S188D-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-A158E-G159E-S188D-A232V-Q245R-N248D-H249R、T022A-S024R-S101G-S103A-V104I-P129E-A158E-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-P129E-A158E-A232V-Q245R-N248D-H249R、T022A-S024R-S101G-S103A-V104I-P129E-A158E-G159E-A232V-Q245R-N248D-H249R、T022A-S024R-S101G-S103A-V104I-P129E-A158E-G159E-S188D-A232V-N238R-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-P129E-A158E-S188D-A232V-N238R-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-P129E-A158E-S188D-A232V-Q245R-N248D-H249R、T022A-S024R-S101G-S103A-V104I-P129E-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-P129E-A232V-Q245R-N248D-H249R、T022A-S024R-S101G-S103A-V104I-P129E-G159E-S188D-A232V-Q245R-N248D-H249R、T022A-S024R-S101G-S103A-V104I-P129E-S188D-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-S128N-A158E-S188D-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-S128N-P129E-A158E-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-S128N-P129E-S188D-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-S128N-S188D-A232V-Q245R-N248D、T022A-S024R-S103A-V104I-G118R-G159D-S188D-L217D-A232V-N248D、T022A-S024R-S103A-V104I-P129E-G159D-S188D-A232V-N248D-E271F、T022A-S101G-S103A-V104I-A158E-G159E-S188D-A232V-Q245R-N248D-H249R、T022A-S101G-S103A-V104I-A158E-S188D-A232V-Q245R-N248D、T022A-S101G-S103A-V104I-P129E-A158E-A232V-N238R-Q245R-N248D、T022A-S101G-S103A-V104I-P129E-A158E-G159E-A232V-N238R-Q245R-N248D、T022A-S101G-S103A-V104I-P129E-A158E-S188D-A232V-Q245R-N248D-H249R、T022A-S101G-S103A-V104I-P129E-G159E-A232V-N238R-Q245R-N248D、T022A-S101G-S103A-V104I-P129E-S188D-A232V-N238R-Q245R-N248D、T022A-S101G-S103A-V104I-S128N-P129E-A232V-N238R-Q245R-N248D、T022A-S101G-S103A-V104I-S128N-P129E-S188D-A232V-N238R-Q245R-N248D、T022A-S128N-A158E-H249R、V104L-S128N-A158E-H249R、V104L-S128N-A158E-R186H-E271F、V104L-S128N-A158E-R186H-H249R、及びV104L-S128N-A158E-S188D-H249Rから選択されるアミノ酸置換の組みを含むアミノ酸配列からなり、このプロテアーゼ変異体の合計正味電荷は、バチルス・レンタスのサブチリシンGG36プロテアーゼの合計正味電荷と比較して0、+1、+2、+3、+4、+5、-1、-2、-3、-4、又は-5であり、合計正味電荷が:N43D、R45T、N62E、N76D、S101D、P129E、A158E、G159D、G159E、S166D、S188D、A230E、N18R、G20K、G20R、T22R、S24R、N43R、G118R、Q245R、H249R、N269R、E271F、及びE271Lから選択された1箇所以上の置換により得られ、プロテアーゼ変異体のアミノ酸位置は、プロテアーゼ変異体のアミノ酸配列を配列番号1で示されるバチルス・アミロリケファシエンスのサブチリシンBPN’のアミノ酸配列と整列させることで決定される、バチルス・アミロリケファシエンスのサブチリシンBPN’の対応するアミノ酸位置に割り振られた番号に従って番号付けされる。
D-S101G-S103A-V104I-G159D-A232V-Q245R-N248D-E271F、T022A-N076D-S101G-S103A-V104I-G159D-S188D-A232V-Q245R-N248D-E271F、T022A-S024R-N043R-S101D-S103A-V104I-G159D-S188D-A232V-Q245R-N248D、T022A-S024R-N043R-S103A-V104I-G159D-S188D-L217D-A232V-N248D-E271F、T022A-S024R-S101D-S103A-V104I-G118R-S128I-G159D-S188D-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-L148I-A158E-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-P129E-A158E-G159E-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-P129E-A158E-G159E-S188D-A232V-Q245R-N248D-H249R、T022A-S024R-S101G-S103A-V104I-P129E-L148I-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-S188D-A232V-Q245R-N248D-H249R、T022A-S024R-S103A-V104I-G118R-P129E-G159D-S188D-A232V-N248D-E271F、T022A-S024R-S103A-V104I-G159D-S188D-L217D-A232V-N248D-E271F、T022A-S024R-S103A-V104I-G159D-S188D-L217D-A232V-Q245R-N248D-E271F、T022A-S101A-A158E-R186H-H249R、T022A-S101G-S103A-V104I-A158E-G159E-A232V-N238R-Q245R-N248D、T022A-S101G-S103A-V104I-A158E-G159E-A232V-Q245R-N248D-H249R、T022A-S101G-S103A-V104I-G159D-A232V-Q245R-N248D-E271F、T022A-S101G-S103A-V104I-G159D-S188D-A232V-Q245R-N248D-H249R-E271F、T022A-S101G-S103A-V104I-G159E-S188D-A232V-N238R-Q245R-N248D、T022A-S101G-S103A-V104I-G159E-S188D-A232V-Q245R-N248D-H249R、T022A-S101G-S103A-V104I-P129E-A158E-A232V-Q245R-N248D-H249R、T022A-S101G-S103A-V104I-P129E-A158E-G159E-A232V-Q245R-N248D-H249R、T022A-S101G-S103A-V104I-P129E-A232V-N238R-Q245R-N248D、T022A-S101G-S103A-V104I-P129E-G159E-A232V-Q245R-N248D-H249R、T022A-S101G-S103A-V104I-P129E-G159E-S188D-A232V-Q245R-N248D-H249R、T022A-S103A-V104I-G118R-G159D-S188D-L217D-A232V-Q245R-N248D、T022A-S103A-V104I-G159D-S188D-A232V-N248D、T022L-L031F-G102A-S128D-T224A-N243F、T022L-T038F-V121F-S160D-A272F、V026F-S078N-G159C-R186K-N243F、V104L-A158E-H249R、V104L-A158E-R186H-H249R、V104L-A158E-R186H-H249R-E271F、V104L-A158E-R186H-S188D-H249R、V104L-A158E-R186H-S188D-H249R-E271F、V104L-A158E-S188D-H249R-E271F、V104L-S128N-A158E-R186H-S188D-E271F、V104L-S128N-G159E-E271F、V104L-S128N-R186H-S188D-H249R、及びV121F-N185E-T224A-P239Gから選択されるアミノ酸置換の組みを含むアミノ酸配列からなり、このプロテアーゼ変異体の合計正味電荷は、バチルス・レンタスのサブチリシンGG36プロテアーゼの合計正味電荷と比較して0、+1、+2、+3、+4、+5、-1、-2、-3、-4、又は-5であり、合計正味電荷が:N43D、R45T、N62E、N76D、S101D、P129E、A158E、G159D、G159E、S166D、S188D、A230E、N18R、G20K、G20R、T22R、S24R、N43R、G118R、Q245R、H249R、N269R、E271F、及びE271Lから選択された1箇所以上の置換により得られ、プロテアーゼ変異体のアミノ酸位置は、ププロテアーゼ変異体のアミノ酸配列を配列番号1で示されるバチルス・アミロリケファシエンスのサブチリシンBPN’のアミノ酸配列と整列させることで決定される、バチルス・アミロリケファシエンスのサブチリシンBPN’の対応するアミノ酸位置に割り振られた番号に従って番号付けされる。
88D-L217D-A232V-N248D-E271F、T022A-S103A-V104I-G118R-G159D-S188D-L217D-A232V-Q245R-N248D-E271F、G020K-N043W-S188D-T213A、S024F-N062E-G118R-P239G、G023A-N043W-S188D-T213A、G020K-S024F-N043W-N062E-N116L-G118R-S188D-P239G、G020K-N116L-S188D-P239G、G020K-N043W-N062E-G118R、G020K-N043W-N116L-S188D-T213A、G020K-S024F、G023A-N043W-N116L-P239G、G023A-S024F-N043W-N116L-G118R-S188D-P239G、G020K-G023A-N043W-T213A、及びG023A-S024F-N062E-G118R-T213A-P239Gから選択されるアミノ酸置換の組みを含むアミノ酸配列からなり、このプロテアーゼ変異体の合計正味電荷は、バチルス・レンタスのサブチリシンGG36プロテアーゼの合計正味電荷と比較して0、+1、+2、+3、+4、+5、-1、-2、-3、-4、又は-5であり、合計正味電荷が:N43D、R45T、N62E、N76D、S101D、P129E、A158E、G159D、G159E、S166D、S188D、A230E、N18R、G20K、G20R、T22R、S24R、N43R、G118R、Q245R、H249R、N269R、E271F、及びE271Lから選択された1箇所以上の置換により得られ、プロテアーゼ変異体のアミノ酸位置は、ププロテアーゼ変異体のアミノ酸配列を配列番号1で示されるバチルス・アミロリケファシエンスのサブチリシンBPN’のアミノ酸配列と整列させることで決定される、バチルス・アミロリケファシエンスのサブチリシンBPN’の対応するアミノ酸位置に割り振られた番号に従って番号付けされる。
、G020R-T022W-S078R-S101G-S103A-V104I-N116A-N183D-G211Q-A232V-Q245R、G020R-T022W-S078R-S101G-S103A-V104I-N116A-N183D-T213A-A232V-Q245R、G020R-T022W-S078R-S101G-S103A-V104I-N116A-T213A-A215F-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-G211Q-A215F-A232V-Q245R、G020R-T022W-S101G-S103A-V104I-A232V-Q245R、G020R-T022W-S101G-S103A-V104I-G211Q-A232V-Q245R、G020R-T022W-S101G-S103A-V104I-I198L-G211Q-T213A-A232V-Q245R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-T213A-A232V-Q245R、G020R-T038A-N043R-S101A、G020R-T22W-S078R-S101A-S103A-V104I-N116A-N183D-A232V、G020R-T22W-S078R-S101G-S103A-V104I-N116A-N183D-A232V-Q245R、G020R-T22W-S078R-S101G-S103A-V104I-N116A-T213A-A215F-A232V-Q245R、G020R-T22W-S101A-S103A-V104I-A215F-A232V-Q245R、G020R-T22W-S101A-S103A-V104I-A232V-Q245R、G020R-T22W-S101A-S103A-V104I-G211Q-T213A-A232V-Q245R、G020R-T22W-S101G-S103A-V104I-A232V-Q245R、G020R-T22W-S101G-S103A-V104I-G211Q-A232V-Q245R、G020R-T22W-S103A-V104I-A232V-Q245R、G023A-P052N-S144R-Y192W-S216F、G023A-P052N-Y192W-I198L-N252R、G023A-S024R-N117F-S212M-S216F、G023A-S078R-S216F-Q236N-H249R、G023A-Y091F-S101A-I198L-N252R、G023A-Y091F-V121F-Y192W-Q236N、G025R-E089I-N116A-P239S-A270C、G025R-G046R-V121F、G025R-N043A-E089I-N117F、G025R-S103N-R186K-A194F-T224A、G046R-A194F-S212M、G046R-E089I-Y091F-S101A-N116A、G046R-E089I-Y192W-L233C-A270C、G046R-N183D-N238L、G046R-Q059A-S103N-G211Q-S212M、G046R-Q059A-S106G-L217E-H249R、L148I-T213A-N252R、N018R-G020R-N043D、N018R-G020R-N043D-A230E-S242R、N018R-G020R-N043D-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-N043D-R045T-A230E、N018R-G020R-N043R-N076D-H249R、N018R-G020R-N043R-N076D-S242R-H249R、N018R-G020R-N043R-R045T-S242R、N018R-G020R-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-R045T、N018R-G020R-S024R-N043D-R045T-L233I-S242R、N018R-G020R-S024R-N043R-R045T-N076D-A230E、N018R-G020R-S024R-N076D-S087D-H249R、N018R-G020R-S024R-N076D-V150L-H249R、N018R-G020R-S024R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-N043D-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-N043D-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-N043D-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、N018R-N043D-S101G-S103A-V104I-A232V-Q245R、N018R-N043D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-N043D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-N043R-N076D-A230E、N018R-N043R-R045T-H249R、N018R-N043R-R045T-S101G-S103A-V104I-A232V-Q245R、N018R-N043R-R045T-S242R-H249R、N018R-N043R-S101G-S103A-V104I-A232V-Q245R、N018R-N043R-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-N043R-S242R-H249R、N018R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-N076D-S101G-V104I-A232V-Q245R、N018R-Q245R、N018R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-R045T-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-R045T-S101G-S103A-V104I-A232V-Q245R、N018R-S024R-N043D-A230E、N018R-S024R-N043D-N076D-H249R、N018R-S024R-N043D-N076D-H249R-N269R、N018R-S024R-N043D-N076D-S078R-H249R、N018R-S024R-N043D-R045T-H249R、N018R-S024R-N043D-S101G-S103A-V104I-A232V-Q245R、N018R-S024R-N043D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-S024R-N043R-N076D-H249R、N018R-S024R-N043R-N076D-H249R-N269R、N018R-S024R-N043R-N076D-S087D-H249R、N018R-S024R-N043R-N076D-V150L-H249R、N018R-S024R-N076D-G211Q-A215F-H249R、N018R-S024R-N076D-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-G211Q-T213A-H249R、N018R-S024R-N076D-H249R、N018R-S024R-N076D-H249R-N269R、N018R-S024R-N076D-N116A-A215F-H249R、N018R-S024R-N076D-N116A-G211Q-A215F-H249R、N018R-S024R-N076D-N116A-G211Q-H249R、N018R-S024R-N076D-N116A-T213A-A215F-H249R、N018R-S024R-N076D-S078R-H249R、N018R-S024R-N076D-S078R-S087D-H249R、N018R-S024R-N076D-S078R-V150L-H249R、N018R-S024R-N076D-S087D-H249R-N269R、N018R-S024R-N076D-S087D-S242R-H249R、N018R-S024R-N076D-S087D-V150L-H249R、N018R-S024R-N076D-S101A-A215F-H249R、N018R-S024R-N076D-S101A-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-S101A-I198L-G211Q-A215V-H249R、N018R-S024R-N076D-S101A-I198L-G211Q-T213A-H249R、N018R-S024R-N076D-S101A-N116A-G211Q-H249R、N018R-S024R-N076D-S101A-N116A-T213A-H249R、N018R-S024R-N076D-S101G-V104I-A232V-H249R、N018R-S024R-N076D-S242R-H249R、N018R-S024R-N076D-T213A-A215F-H249R、N018R-S024R-N076D-V104I-H249R、N018R-S024R-N076D-V150L-H249R、N018R-S024R-R045T-S242R、N018R-S024R-S101G-V104I、N018R-S024R-S101G-V104I-A232V、N018R-S024R-S242R、N018R-S024R-V104I-H249R、N018R-S024R-V244R、N018R-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-S087D-S101G-S103A-V104I-A232V-Q245R、N018R-S101G-Q245R、N018R-S101G-S103A-H249R、N018R-S101G-S103A-Q245R、N018R-S101G-S103A-V104I-A232V-Q245R、N018R-S101G-S103A-V104I-V150L-A232V-Q245R、N018R-S101G-V104I-A232V-H249R、N018R-S101G-V104I-A232V-Q245R、N018R-S101G-V104I-H249R、N018R-S103A-A232V-H249R、N018R-S103A-V104I-H249R、N018R-T022R-S024R-N043D-N076D-H249R、N018R-T022R-S024R-N043R-N076D-H249R、N018R-T022R-S024R-N076D-H249R、N018R-T022R-S024R-N076D-S087D-H249R、N018R-T022R-S024R-N076D-V150L-H249R、N018R-T022W-S024R-N076D-N116A-G211Q-H249R、N018R-T022W-S024R-N076D-N116A-T213A-H249R、N018R-T022W-S024R-N076D-S101A-I198L-A215F-H249R、N018R-T022W-S024R-N076D-S101A-I198L-H249R、N018R-T022W-S024R-N076D-S101A-N116A-A232V-Q245R、N018R-T22K-N043D-S101G-S103A-V104I-A232V-Q245R、N018R-T22W-S024R-N076D-N116A-T213A-H249R、N018R-T22W-S024R-N076D-S101A-N116A-A232V-Q245R、N0
18R-V104I-A232V-H249R、N043A-N062Q-A194F-G211Q、N043A-T057R-N117F-S144R-N183D、N043D-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N043D-R045T-N076D-H249R、N043D-S078R-S101G-S103A-V104I-A232V-Q245R、N043D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N043D-S101G-S103A-V104I-A232V-Q245R-N269R、N043R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N043R-N076D-S101G-S103A-V104I-A232V-Q245R、N043R-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N043R-N076D-S242R-H249R、N043R-N116A-N269R、N043R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N043R-R045T-S078R-S101G-S103A-V104I-A232V-Q245R、N043R-R045T-S101G-S103A-V104I-A232V-Q245R-N269R、N043R-S078R-S101G-S103A-V104I-A232V-Q245R、N043R-S087D-S101G-S103A-V104I-A232V-Q245R-N269R、N043R-S101A-N116A-A215F-N269R、N043R-S101A-N116A-N269R、N043R-S101A-N116A-T213A-A215F-N269R、N043R-S101A-N269R、N043R-S101A-T213A-N269R、N043R-S101G-S103A-V104I-A232V-Q245R、N043R-S101G-S103A-V104I-A232V-Q245R-E271L、N043R-S101G-S103A-V104I-A232V-Q245R-H249R、N043R-S101G-S103A-V104I-A232V-Q245R-N269R、N043R-S101G-S103A-V104I-A232V-S242R-Q245R、N043R-S101G-S103A-V104I-V150L-A232V-Q245R、N043R-S242R-H249R、N043R-T213A-A215F-N269R、N062Q-S103N-N117F-A194F、N062Q-S103N-V121F-S144R-H249R、N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N076D-S101G-S103A-V104I-A232V-Q245R、N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N076D-S103A-V104I-Q109R、N076D-S103A-V104I-Q109R-Q245R、N076D-S103A-V104I-S212P-E271V、N076D-S103A-V104I-S212P-Q245L-E271V、N076D-S87R-S103A-V104I-S212P-E271V、N117F-A194F-T213A-A270C、N117F-T213A-A215F、P052N-S078R-S103N-L148I-T213A、P052N-S103N-N116A-L148I-Y192W、R019H-G020R-T022W-S078R-S101G-S103A-V104I-G211Q-A232V-Q245R、R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、R045T-S078R-S101G-S103A-V104I-A232V-Q245R、R045T-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、S009A-G020R-N043R-S212F、S009A-G020R-N043R-W241R、S009A-G020R-S024R-N043R、S009A-N043R-S078R、S009A-N043R-S078R-S242R、S009A-N043R-S212F、S009A-N043R-W241R、S009A-T022R-N043R-S078R、S009A-T022R-S078R-S212F、S009A-T022R-S078R-S212F-W241R、S009A-T022R-S212F-W241R、S024R-A215F-N269R、S024R-A232V-Q245R、S024R-G025R-N183D-Y192W-P239S、S024R-N043A-N117F-A194F-G211Q、S024R-N043D-H249R、S024R-N043D-S101G-S103A-V104I-A232V-Q245R-H249R、S024R-N043D-S101G-S103A-V104I-A232V-Q245R-N269R、S024R-N043R-A215F、S024R-N043R-A230E、S024R-N043R-A230E-S242R、S024R-N043R-H249R、S024R-N043R-N076D-H249R、S024R-N043R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、S024R-N043R-N076D-S101G-S103A-V104I-A232V-Q245R、S024R-N043R-N116A-A215F、S024R-N043R-N116A-A215F-N269R、S024R-N043R-N116A-N269R、S024R-N043R-N116A-T213A-N269R、S024R-N043R-R045T-N076D-A230E-H249R、S024R-N043R-R045T-N269R、S024R-N043R-R045T-S101A-N116A-A215F-N269R、S024R-N043R-R045T-S101A-N116A-T213A-N269R、S024R-N043R-R045T-S242R、S024R-N043R-R045T-T213A-A215F-N269R、S024R-N043R-S101A-A215F、S024R-N043R-S101A-A215F-N269R、S024R-N043R-S101A-N116A、S024R-N043R-S101A-N116A-A215F-N269R、S024R-N043R-S101G-S103A-V104I-A232V-Q245R、S024R-N043R-S242R、S024R-N062Q-V104L-S106G-H249R、S024R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、S024R-N076D-V104I-A232V-Q245R、S024R-N116A-T213A-N269R、S024R-R045T、S024R-R045T-N076D-A230E-S242R-H249R、S024R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、S024R-R045T-S101G-S103A-V104I-A232V-Q245R-N269R、S024R-S078R-S212F、S024R-S078R-V104L-N116A-N183D、S024R-S087D-S101G-S103A-V104I-A232V-Q245R、S024R-S101A-H120F-A194F-H249R、S024R-S101A-N269R、S024R-S101G-S103A-V104I-A232V-Q245R、S024R-S101G-S103A-V104I-V150L-A232V-Q245R、S024R-S101G-V104I-Q245R、S024R-S103A-Q245R、S024R-S103A-V104I-A232V-H249R、S024R-S103A-V104I-H249R、S024R-S103A-V104I-Q245R、S024R-Y167W-T224A-H249R、S078R-S087D-S101G-S103A-V104I-A232V-Q245R、S078R-S101G-S103A-V104I-A232V-Q245R、S078R-S101G-S103A-V104I-A232V-Q245R-N269R、S078R-S101G-S103A-V104I-V150L-A232V-Q245R、S078R-S103N-S106G-Y167W-Q236N、S078R-V104L-T213A-A215F-T224A、S078R-Y091F-V121F-L233C-N252R、S087D-S101G-S103A-V104I-A232V-Q245R-N269R、S087R-S101G-S103A-V104I-Q109R-S212P-A232V-Q245R-E271V、S099F-S144R-Y167W-N252R、S101A-H120F-Y192W-A215F-T224A、S101A-S103A-V104I-T213A-A232V-Q245R-N269R、S101G-S103A-V104I-A232V-Q245R、S101G-S103A-V104I-A232V-Q245R-E271L、S101G-S103A-V104I-A232V-Q245R-H249R、S101G-S103A-V104I-A232V-Q245R-N269R、S101G-S103A-V104I-A232V-Q245R-N269R、S101G-S103A-V104I-A232V-S242R-Q245R、S101G-S103A-V104I-A232V-V244R-Q245R、S101G-S103A-V104I-G115R-A232V-Q245R、S101G-S103A-V104I-N116A-T213A-A232V-Q245R-N269R、S101G-S103A-V104I-Q109R-A232V-Q245R、S101G-S103A-V104I-Q109R-S212P-A232V-Q245R、S101G-S103A-V104I-Q109R-S212P-A232V-Q245R-E271V、S101G-S103A-V104I-S212F-A232V-Q245R、S101G-S103A-V104I-V150L-A232V-Q245R-H249R、S101G-S103A-V104I-V150L-A232V-Q245R-N269R、S105T-S128N-S144R-L148I-S212M、S106G-N117F-N238L、S144R-G211Q-N238L-P239S-H249R、T022R-N043R-S101G-S103A-V104I-A232V-Q245R、T022R-N076D-S101G-S103A-V104I-A232V-Q245R、T022R-S087D-S101G-S103A-V104I-A232V-Q245R、T022R-S101G-S103A-V104I-A232V-Q245R、T022W-S078R-Y167W-S212M-A270C、T057R-E089I-I198L、T057R-S099F-S105T-I198L-T213A、T057R-S099F-V121F-N185I-Y192W、T057R-Y167W-H249R、V004R-G020R-H249R、V004R-G020R-N043R、V004R-G020R-S024R、V004R-G020R-S024R-H249R、V004R-G020R-S024R-N043R、V004R-G020R-S024R-
N043R-S242R、V004R-G020R-S024R-V244R、V004R-N043R-S101G-S103A-V104I-A232V-Q245R、V004R-S009A-G020R-N043R、V004R-S009A-G020R-N043R-S242R、V004R-S009A-G020R-S024R-S242R、V004R-S009A-G020R-S242R、V004R-S009A-N043R-W241R、V004R-S009A-S024R-N043R-W241R、V004R-S009A-S078R-W241R、V004R-S009A-W241R、V004R-S101G-S103A-V104I-A232V-Q245R、V104L-L217E-T224A-H249R-N252R、V104L-T213A-S216F、V121F-N252R-A270C、及びY091F-S099F-S101A-S105T-Y167Wから選択されるアミノ酸置換の組みを含むアミノ酸配列からなり、このプロテアーゼ変異体の合計正味電荷は、バチルス・レンタスのサブチリシンGG36プロテアーゼの合計正味電荷と比較して0、+1、+2、+3、+4、+5、-1、-2、-3、-4、又は-5であり、合計正味電荷が:N43D、R45T、N62E、N76D、S101D、P129E、A158E、G159D、G159E、S166D、S188D、A230E、N18R、G20K、G20R、T22R、S24R、N43R、G118R、Q245R、H249R、N269R、E271F、及びE271Lから選択された1箇所以上の置換により得られ、プロテアーゼ変異体のアミノ酸位置は、ププロテアーゼ変異体のアミノ酸配列を配列番号1で示されるバチルス・アミロリケファシエンスのサブチリシンBPN’のアミノ酸配列と整列させることで決定される、バチルス・アミロリケファシエンスのサブチリシンBPN’の対応するアミノ酸位置に割り振られた番号に従って番号付けされる。
H249R、N018R-G020R-R045T-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-S024R-N043D-N076D-S242R、N018R-G020R-S024R-N043D-R045T-S242R、N018R-G020R-S024R-N043R-N076D-H249R、N018R-G020R-S024R-N043R-R045T-N076D-H249R、N018R-G020R-S024R-N076D-A215F-H249R、N018R-G020R-S024R-N076D-G211Q-A215F-H249R、N018R-G020R-S024R-N076D-L217E-H249R、N018R-G020R-S024R-N076D-N116A-A215F-H249R、N018R-G020R-S024R-N076D-N116A-N183D-A215F-H249R、N018R-G020R-S024R-N076D-N116A-N183D-I198L-G211Q-H249R、N018R-G020R-S024R-N076D-N116A-N183D-T213A-A215F-H249R、N018R-G020R-S024R-N076D-N183D-H249R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-I198L-H249R、N018R-G020R-S024R-N076D-S101A-N183D-G211Q-A215F-H249R、N018R-G020R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-I198L-T213A-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-N183D-H249R、N018R-G020R-T22W-S024R-N076D-N116A-N183D-I198L-T213A-H249R、N018R-N043D-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-N043D-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-N043D-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-N043D-R045T-N076D-S242R-H249R、N018R-N043D-R045T-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-N043D-R045T-S101G-S103A-V104I-A232V-Q245R、N018R-N043D-R045T-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-N043D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-N043R-N076D-A230E-S242R-H249R、N018R-N043R-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-N043R-N076D-S242R-H249R、N018R-N043R-R045T-N076D-A230E-S242R、N018R-N043R-R045T-N076D-S076T-S101G-S103A-V104I-A232V-Q245R-A273T、N018R-N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-N043R-R045T-N076D-S242R、N018R-N043R-R045T-S242R、N018R-N076D-H249R、N018R-N076D-Q245R、N018R-N076D-S101G-A232V-Q245R、N018R-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-N076D-S101G-S103A-V104I-H249R、N018R-N076D-S101G-V104I-H249R、N018R-N076D-S103A-V104I-H249R、N018R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-S024R-N043D-A230E-H249R、N018R-S024R-N043D-A230E-S242R、N018R-S024R-N043D-H249R、N018R-S024R-N043D-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-S024R-N043D-N076D-S242R-H249R、N018R-S024R-N043D-N076D-V150L-H249R、N018R-S024R-N043D-S242R、N018R-S024R-N043D-S242R-H249R、N018R-S024R-N043R-N076D-L217E-H249R、N018R-S024R-N043R-N076D-S078R-H249R、N018R-S024R-N043R-R045T-A230E-H249R、N018R-S024R-N076D、N018R-S024R-N076D-A232V-H249R、N018R-S024R-N076D-G211Q-H249R、N018R-S024R-N076D-I198L-G211Q-A215F-H249R、N018R-S024R-N076D-I198L-G211Q-T213A-H249R、N018R-S024R-N076D-I198L-T213A-A215F-H249R、N018R-S024R-N076D-I198M-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-L088I-S101A-N116A-I198L-G211Q-A215F-H249R、N018R-S024R-N076D-N116A-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-N116A-H249R、N018R-S024R-N076D-N116A-I198L-A215F-H249R、N018R-S024R-N076D-N116A-I198L-A215F-H249R-V268G、N018R-S024R-N076D-N116A-I198L-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-N116A-I198L-G211Q-T213A-H249R、N018R-S024R-N076D-N116A-I198L-H249R、N018R-S024R-N076D-N116A-I198L-T213A-H249R、N018R-S024R-N076D-N116A-I198L-Y209H-T213A-H249R、N018R-S024R-N076D-N116A-M117I-N183D-T213A-H249R、N018R-S024R-N076D-N116A-N183D-G211Q-H249R、N018R-S024R-N076D-N116A-T213A-H249R、N018R-S024R-N076D-N183D-I198L-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-N183D-T213A-A215F-H249R、N018R-S024R-N076D-S101A-G211Q-A215F-H249R、N018R-S024R-N076D-S101A-G211Q-H249R、N018R-S024R-N076D-S101A-H249R、N018R-S024R-N076D-S101A-I198L-A215F-H249R、N018R-S024R-N076D-S101A-I198L-G211Q-H249R、N018R-S024R-N076D-S101A-I198L-H249R、N018R-S024R-N076D-S101A-I198L-T213A-H249R、N018R-S024R-N076D-S101A-N116A-G211Q-T213A-H249R、N018R-S024R-N076D-S101A-N116A-I198L-G211Q-H249R、N018R-S024R-N076D-S101A-N116A-I198L-G211Q-T213A-H249R、N018R-S024R-N076D-S101A-N116A-I198L-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N116A-N183D-I198L-T213A-H249R、N018R-S024R-N076D-S101A-N116A-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N183D-G211Q-H249R、N018R-S024R-N076D-S101A-N183D-T213A-H249R、N018R-S024R-N076D-S101G-A232V、N018R-S024R-N076D-S103A-A232V-Q245R、N018R-S024R-N076D-T213A-H249R、N018R-S024R-N076D-V104I、N018R-S024R-Q245R、N018R-S024R-R045T-A230E-S242R、N018R-S024R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-S024R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-S024R-S242R、N018R-S024R-V104I、N018R-S024R-V30S-L31S-D32I-T33Q-G34V-I35F、N018R-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、N018R-S101G-S103A-V104I、N018R-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-S101G-V104I、N018R-S103A、N018R-S103A-V104I-A232V、N018R-T022K-N043D-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-G211Q-H249R、N018R-T022W-S024R-N076D-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-I198L-A215F-H249R、N018R-T022W-S024R-N076D-I198L-G211Q-H249R、N018R-T022W-S024R-N076D-I198L-T213A-A215F-H249R、N018R-T022W-S024R-N076D-N116A-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-N116A-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-N116A-I198L-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-N116A-I198L-T213A-H249R、N018R-T022W-S024R-N076D-N116A-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-G211Q-H249R、N018R-T022W-S024R-N076D-S101A-G211Q-T213A-H249R、N018
R-T022W-S024R-N076D-S101A-I198L-G211Q-Q245R、N018R-T022W-S024R-N076D-S101A-I198L-G211Q-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-I198L-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-G211Q-H249R、N018R-T022W-S024R-N076D-S101A-N116A-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N116A-I198L-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-I198L-G211Q-H249R、N018R-T022W-S024R-N076D-S101A-N116A-I198L-G211Q-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-I198L-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N116A-I198L-H249R、N018R-T022W-S024R-N076D-S101A-N116A-I198L-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-I198L-T213A-H249R、N018R-T022W-S024R-N076D-S101A-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-T213A-H249R、N018R-T022W-S024R-N076D-T213A-A215F-H249R、N018R-T22W-S024R-N076D-I198L-A215F-H249R、N018R-T22W-S024R-N076D-N116A-G211Q-H249R、N018R-T22W-S024R-N076D-N116A-G211Q-T213A-H249R、N018R-T22W-S024R-N076D-N116A-T213A-A215F-H249R、N018R-T22W-S024R-N076D-S101A-A215F-H249R、N018R-T22W-S024R-N076D-S101A-G211Q-T213A-H249R、N018R-T22W-S024R-N076D-S101A-I198L-A215F-H249R、N018R-T22W-S024R-N076D-S101A-I198L-T213A-A215F-H249R、N018R-T22W-S024R-N076D-S101A-N116A-A215F-H249R、N018R-T22W-S024R-N076D-S101A-N116A-I198L-A215F-H249R、N018R-T22W-S024R-N076D-T213A-A215F-H249R、N018R-V104I、N043D-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N043D-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N043D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R-A272V、N043D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R-R275S、N043D-S101G-S103A-V104I-A232V-Q245R、N043D-S101G-S103A-V104I-A232V-Q245R-H249R、N043R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N043R-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、N043R-N076D-S101G-S103A-V104I-L217E-A232V-Q245R、N043R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N043R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-V234I-Q245R、N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N043R-R045T-S078R-S101G-S103A-V104I-N218S-A232V-Q245R、N043R-R045T-S101G-S103A-V104I-A232V-Q245R、N043R-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N043R-S087D-S101G-S103A-V104I-A232V-Q245R、N062Q-S101A-Q236N-N252R-A270C、N076D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N076D-S101G-S103A-V104I-A232V-Q245R-H249R、N076D-S101G-S103A-V104I-A232V-S242R-Q245R、P005S-S024R-T033S-N243F、P014L-G020R-S024R-N043R-R045T-S101A-A215F、P052N-V104L-N183D-S216F-H249R、P086W-G118R、P086W-N243F、P086W-Y209A、Q012H-G020R-S078R-S101G-S103A-V104I-I198L-G211Q-T213A-A232V-Q245R、R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、R045T-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、R045T-S101G-S103A-V104I-A232V-Q245R-N269R、R045T-S242R-H249R、S024C-T033S、S024R-A232V、S024R-G046R-Y091F-V121F、S024R-G118R-K235F、S024R-N043A-S105T-S106G-I198L、S024R-N043D-R045T-S242R-H249R、S024R-N043D-S101G-S103A-V104I-A232V-Q245R、S024R-N043D-S242R-H249R、S024R-N043R-N076D、S024R-N043R-N076D-A230E-S242R、S024R-N043R-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、S024R-N043R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、S024R-N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、S024R-N043R-R045T-S242R-H249R、S024R-N043R-S101A-T213A、S024R-N076D-Q245R、S024R-N076D-S101G-A232V-Q245R、S024R-N076D-S101G-M175L-A232V-Q245R、S024R-N076D-S101G-Q245R、S024R-N076D-S101G-S103A-V104I-A232V-Q245R、S024R-N076D-S103A-V104I-Q245R、S024R-N076D-V104I-Q245R、S024R-N243F、S024R-P086R-G118R、S024R-P086W-Y209A-K235F、S024R-P239Q、S024R-Q245R-H249R、S024R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、S024R-S101G、S024R-S101G-Q245R、S024R-S101G-V104I-H249R、S024R-S103A-A232V、S024R-S103A-M175L-A232V-H249R、S024R-S141G、S024R-T033S、S024R-T033S-A194T、S024R-T033S-G118R-K235F、S024R-T033S-G118R-Y209A、S024R-T033S-K235F、S024R-T033S-S078R-G118R、S024R-T033S-S078R-N243F、S024R-T033S-Y209A、S024R-T033S-Y209A-N243F、S024R-T274I、S024R-V104I-H249R、S024R-V104I-Q245R、S024R-Y091F-I198L-A215F-P239S、S024R-Y209A、S024R-Y209A-K235F、S024R-Y209A-S242P、S078R-P086W、S078R-S099F-N116A-R186K-T224A、S078R-S101G-S103A-V104I-A232V-Q245R-H249R、S101G-A232V、S101G-S103A-V104I-A232V-H249R、S101G-S103A-V104I-A232V-Q245R-H249R-N269R、S101G-S103A-V104I-Q245R、S105T-G211Q-S216F、S106G-N185I-S216F-Q236N、T022R-S101G-S103A-V104I-V150L-A232V-Q245R、T033S-G118D-A138V-Y209A、T033S-G118R-Y209A-、T033S-L148F、T033S-N243F、T033S-P086W、T033S-P201S、T033S-S078R、T033S-W241R、T033S-Y209A、T033S-Y209A-K235F、V004M-N018R-S024R-N076D-N116A-I198L-G211Q-T213A-H249R、V104I-A232V-H249R、及びV104L-H120F-R186K-S216F-N252Rから選択されるアミノ酸置換の組みを含むアミノ酸配列からなり、このプロテアーゼ変異体の合計正味電荷は、バチルス・レンタスのサブチリシンGG36プロテアーゼの合計正味電荷と比較して0、+1、+2、+3、+4、+5、-1、-2、-3、-4、又は-5であり、合計正味電荷が:N43D、R45T、N62E、N76D、S101D、P129E、A158E、G159D、G159E、S166D、S188D、A230E、N18R、G20K、G20R、T22R、S24R、N43R、G118R、Q245R、H249R、N269R、E271F、及びE271Lから選択された1箇所以上の置換により得られ、プロテアーゼ変異体のアミノ酸位置は、ププロテアーゼ変異体のアミノ酸配列を配列番号1で示されるバチルス・アミロリケファシエンスのサブチリシンBPN’のアミノ酸配列と整列させることで決定される、バチルス・アミロリケファシエンスのサブチリシンBPN’の対応するアミノ酸位置に割り振られた番号に従って番号付けされる。
A-H249R、N018R-G020R-S024R-N076D-S101A-I198L-T213A-A215F-H249R、N018R-G020R-S024R-N076D-S101A-N116A-G211Q-T213A-A215F-H249R、N018R-G020R-S024R-N076D-S101A-N116A-G211Q-T213A-H249R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-G211Q-A215F-H249R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-G211Q-T213A-H249R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-H249R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-A215F-H249R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-I198L-T213A-H249R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-T213A-H249R、N018R-G020R-S024R-N076D-S101A-N116A-T213A-A215F-H249R、N018R-G020R-S024R-N076D-S101A-N116A-T213A-H249R、N018R-G020R-S024R-N076D-S101A-N183D-G211Q-H249R、N018R-G020R-S024R-N076D-S101A-N183D-I198L-A215F-H249R、N018R-G020R-S024R-N076D-S101A-N183D-I198L-G211Q-T213A-H249R、N018R-G020R-S024R-N076D-S101A-N183D-I198L-T213A-H249R、N018R-G020R-S024R-N076D-S101A-N183D-T213A-A215F-H249R、N018R-G020R-S024R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-S024R-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-I198L-T213A-H249R、N018R-G020R-T022W-S024R-N076D-N116A-I198L-H249R、N018R-G020R-T022W-S024R-N076D-N116A-I198L-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-G211Q-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-I198L-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-T213A-H249R、N018R-G020R-T022W-S024R-N076D-N183D-G211Q-T213A-H249R、N018R-G020R-T022W-S024R-N076D-N183D-I198L-G211Q-H249R、N018R-G020R-T022W-S024R-N076D-S101A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-G211Q-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-G211Q-T213A-H249R、N018R-G020R-T022W-S024R-N076D-S101A-I198L-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-I198L-G211Q-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-G211Q-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-I198L-G211Q-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-I198L-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-N183D-G211Q-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-N183D-G211Q-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-T213A-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-N183D-T213A-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-T213A-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N183D-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N183D-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-T213A-H249R、N018R-N043D-A230E-H249R、N018R-N043D-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-N043D-N076D-S242R-H249R、N018R-N043D-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-N043D-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-N043D-R045T-S078R-S101G-S103A-V104I-A232V-Q245R-A272D、N018R-N043R-N076D-A230E-H249R、N018R-N043R-N076D-S242R、N018R-N043R-R045T-A230E-S242R、N018R-N043R-R045T-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、N018R-N043R-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-N043R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-N076D-A232V-H249R、N018R-N076D-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、N018R-N076D-S101G-I198T-A232V、N018R-N076D-S101G-S103A-V104I-Q245R、N018R-N076D-S101G-V104I、N018R-N076D-S242R、N018R-N076D-S242R-H249R、N018R-N076D-V104I-Q245R-H249R、N018R-R045T-H249R、N018R-R045T-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-R045T-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-S024R-N043D-N076D-S087D-H249R、N018R-S024R-N043D-N076D-S242R、N018R-S024R-N076D-A086V-S101A-N183D-I198L-G211Q-H249R、N018R-S024R-N076D-A215F-H249R、N018R-S024R-N076D-A232V、N018R-S024R-N076D-I198L-A215F-H249R、N018R-S024R-N076D-I198L-G211Q-H249R、N018R-S024R-N076D-I198L-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-I198L-H249R、N018R-S024R-N076D-I198L-T213A-H249R、N018R-S024R-N076D-L217E-H249R-N269R、N018R-S024R-N076D-N116A-A150T-T213A-H249R、N018R-S024R-N076D-N116A-G211Q-T213A-H249R、N018R-S024R-N076D-N116A-I198L-G211Q-H249R、N018R-S024R-N076D-N116A-I198L-T213A-A215F-H249R、N018R-S024R-N076D-N116A-N183D-A215F-H249R、N018R-S024R-N076D-N116A-N183D-G211Q-A215F-H249R、N018R-S024R-N076D-N116A-N183D-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-N116A-N183D-G211Q-T213A-H249R、N018R-S024R-N076D-N116A-N183D-H249R、N018R-S024R-N076D-N116A-N183D-I198L-A215F-H249R、N018R-S024R-N076D-N116A-N183D-I198L-G211Q-A215F-H249R、N018R-S024R-N076D-N116A-N183D-I198L-G211Q-H249R、N018R-S024R-N076D-N116A-N183D-I198L-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-N116A-N183D-I198L-G211Q-T213A-H249R、N018R-S024R-N076D-N116A-N183D-I198L-H249R、N018R-S024R-N076D-N116A-N183D-I198L-T213A-H249R、N018R-S024R-N076D-N116A-N183D-T213A-A215F-H249R、N018R-S024R-N076D-N116A-N183D-T213A-H249R、N018R-S024R-N076D-N183D-A215F-H249R、N018R-S024R-N076D-N183D-G211Q-H249R、N018R-S024R-N076D-N183D-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-N183D-G211Q-T213A-H249R、N018R-S024R-N076D-N183D-H249R、N018R-S024R-N076D-N183D-H249R-A248T、N018R-S024R-N076D-N183D-I198L-A215F-H249R、N018R-S024R-N076D-N183D-I198L-G211Q-A215F-H249R、N018R-S024R-N076D-N183D-I198L-G211Q-H
249R、N018R-S024R-N076D-N183D-I198L-H249R、N018R-S024R-N076D-N183D-I198L-T213A-A215F-H249R、N018R-S024R-N076D-N183D-I198L-T213A-H249R、N018R-S024R-N076D-N183D-T213A-H249R、N018R-S024R-N076D-S087D-H249R、N018R-S024R-N076D-S101A-G211Q-T213A-A215F-H249R-A270V、N018R-S024R-N076D-S101A-G211Q-T213A-H249R、N018R-S024R-N076D-S101A-I198L-G211Q-A215F-H249R、N018R-S024R-N076D-S101A-N116A-G211Q-A215F-H249R、N018R-S024R-N076D-S101A-N116A-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N116A-H249R、N018R-S024R-N076D-S101A-N116A-I198L-G211Q-A215F-H249R、N018R-S024R-N076D-S101A-N116A-I198L-H249R、N018R-S024R-N076D-S101A-N116A-I198L-T213A-H249R、N018R-S024R-N076D-S101A-N116A-N183D-A215F-H249R、N018R-S024R-N076D-S101A-N116A-N183D-G211Q-A215F-H249R、N018R-S024R-N076D-S101A-N116A-N183D-G211Q-H249R、N018R-S024R-N076D-S101A-N116A-N183D-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N116A-N183D-G211Q-T213A-H249R、N018R-S024R-N076D-S101A-N116A-N183D-H249R、N018R-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-T213A-H249R、N018R-S024R-N076D-S101A-N116A-N183D-I198L-H249R、N018R-S024R-N076D-S101A-N116A-N183D-I198L-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N116A-N183D-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N116A-N183D-T213A-H249R、N018R-S024R-N076D-S101A-N183D-A215F-H249R、N018R-S024R-N076D-S101A-N183D-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N183D-H249R、N018R-S024R-N076D-S101A-N183D-I198L-A215F-H249R、N018R-S024R-N076D-S101A-N183D-I198L-G211Q-H249R、N018R-S024R-N076D-S101A-N183D-I198L-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N183D-I198L-G211Q-T213A-H249R、N018R-S024R-N076D-S101A-N183D-I198L-H249R、N018R-S024R-N076D-S101A-N183D-I198L-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N183D-I198L-T213A-H249R、N018R-S024R-N076D-S101A-N183D-T213A-A215F-H249R、N018R-S024R-N076D-S101A-T213A-A215F-H249R、N018R-S024R-N076D-S101A-V197A-T213A-A215F-H249R、N018R-S024R-N076D-S101G、N018R-S024R-N076D-S101G-Q245R、N018R-S024R-N076D-S101G-S103A-V104I-A232V、N018R-S024R-N076D-S103A-H249R、N018R-S024R-N076D-S103A-V104I-L135I-A232V、N018R-S024R-N076D-T213A-A215F-H249R-T260K、N018R-S024R-N076D-V150L-S242R-H249R、N018R-S024R-R045T-A230E-H249R、N018R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-T022R-S024R-N076D-S101A-N116A-N183D-G211Q-H249R、N018R-T022W-S024R-N076D-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-I198L-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-I198L-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-I198L-H249R、N018R-T022W-S024R-N076D-I198L-T213A-H249R、N018R-T022W-S024R-N076D-N116A-A215F-H249R、N018R-T022W-S024R-N076D-N116A-G211Q-T213A-A215F-H249R、N018R-T022W-S024R-N076D-N116A-H249R、N018R-T022W-S024R-N076D-N116A-I198L-A215F-H249R、N018R-T022W-S024R-N076D-N116A-I198L-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-N116A-I198L-G211Q-T213A-A215F-H249R、N018R-T022W-S024R-N076D-N116A-I198L-H249R、N018R-T022W-S024R-N076D-N116A-I198L-T213A-A215F-H249R、N018R-T022W-S024R-N076D-N116A-N183D-A215F-H249R、N018R-T022W-S024R-N076D-N116A-N183D-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-N116A-N183D-G211Q-H249R、N018R-T022W-S024R-N076D-N116A-N183D-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-N116A-N183D-G211Q-T213A-Q245R、N018R-T022W-S024R-N076D-N116A-N183D-I198L-A215F-H249R、N018R-T022W-S024R-N076D-N116A-N183D-I198L-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-N116A-N183D-I198L-G211Q-H249R、N018R-T022W-S024R-N076D-N116A-N183D-I198L-G211Q-T213A-A209V-H249R、N018R-T022W-S024R-N076D-N116A-N183D-I198L-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-N116A-N183D-I198L-H249R、N018R-T022W-S024R-N076D-N116A-N183D-I198L-Y209H-G211Q-H249R、N018R-T022W-S024R-N076D-N116A-N183D-T213A-A215F-H249R、N018R-T022W-S024R-N076D-N116A-N183D-T213A-H249R、N018R-T022W-S024R-N076D-N183D-G211Q-H249R、N018R-T022W-S024R-N076D-N183D-G211Q-T213A-A215F-H249R、N018R-T022W-S024R-N076D-N183D-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-N183D-H249R、N018R-T022W-S024R-N076D-N183D-I198L-A215F-H249R、N018R-T022W-S024R-N076D-N183D-I198L-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-N183D-I198L-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-N183D-I198L-H249R、N018R-T022W-S024R-N076D-N183D-T213A-H249R、N018R-T022W-S024R-N076D-S101A-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-S101A-I198L-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-S101A-I198L-G211Q-H249R、N018R-T022W-S024R-N076D-S101A-I198L-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N116A-G211Q-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-G211Q-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-G211Q-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N116A-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-T213A-A215F-H249R-L267I、N018R-T022W-S024R-N076D-S101A-N116T-I198L-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N183
D-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N183D-G211Q-H249R、N018R-T022W-S024R-N076D-S101A-N183D-G211Q-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N183D-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N183D-I198L-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N183D-I198L-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N183D-I198L-Y209H-H249R、N018R-T022W-S024R-N076D-S101A-N183D-T213A-A215F-H249R、N018R-T22W-S024R-N076D-G211Q-T213A-H249R、N018R-T22W-S024R-N076D-N116A-I198L-T213A-H249R、N018R-T22W-S024R-N076D-S101A-I198L-H249R、N018R-V104I-A232V、N043A-Q059A-S101A-S216F-T224A、N043D-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、N043D-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N043D-R045T-S078R-S101G-S103A-V104I-A232V-Q245R、N043D-R045T-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N043D-S242R-H249R、N043R-A230E-H249R、N043R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N043R-N076D-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、N043R-N076D-S101G-S103T-V104I-A232V-Q245R-H249R-N269R、N043R-R045T-H249R、N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N043R-R045T-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N043R-R045T-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、N043R-R045T-S101G-S103A-V104I-A232V-Q245R-H249R、N043R-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、N043R-S101G-S103A-V104I-Q245R-H249R、N043R-S101G-S103A-V104I-V150L-A232V-Q245R-N269R、N076D-A232V-Q245R、N076D-Q245R、N076D-S101G-A232V-Q245R、N076D-S101G-S103A-Q245R、N076D-S101G-S103A-V104I-A232V-H249R、N076D-S101G-S103A-V104I-H249R、N076D-S101G-S103A-V104I-V150L-A232V-Q245R、N076D-S101G-V104I-H249R、N076D-S101G-V104I-Q245R、N076D-S103A-V104I-A232V-Q245R、N076D-S103A-V104I-Q245R、N076D-V104I-A232V-Q245R、N076D-V104I-Q245R、P005S-N018R-T022W-S024R-N076D-S101A-T213A-A215F-H249R、P086W-K235F、P086W-Y209A-K235F、Q012H-V104A-G118R、R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、R045T-S101G-S103A-V104I-A232V-Q245R、S024R-G118R-N243F-R269H、S024R-K235F-N243F、S024R-N043D-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、S024R-N043R-N076D-A230E-H249R、S024R-N076D-A232V-H249R、S024R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、S024R-N076D-S101G、S024R-N076D-S101G-A232V-H249R、S024R-N076D-S101G-S103A-A232V、S024R-N076D-S101G-S103A-V104I-M175L-H249R、S024R-N076D-S101G-S103A-V104I-Q245R、S024R-N076D-S101G-V104I-A232V-H249R、S024R-N076D-S103A-H249R、S024R-N076D-S103A-Q245R、S024R-N076D-S103A-V104I-H249R、S024R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、S024R-R045T-S242R-A273V、S024R-R247H、S024R-S101G-S103A、S024R-S101G-S103A-A232V、S024R-S101G-S103A-V104I、S024R-S103A-Q245R-H249R、S024R-S103A-V104I、S024R-S106G-N116A-S212M-T224A、S024R-T033S-A151V、S024R-T033S-A174V-K235F、S024R-T033S-A228T、S024R-T033S-K235F-W241R、S024R-T033S-N243F、S024R-V104A、S024R-V104I-A232V、S024R-Y209A-N243F、S078R-K235F、S087D-S101G-S103A-V104I-A232V-S242R-Q245R、S099F-S105T-S106G-A194F-S212M、S101G-H249R、S101G-S103A-V104I、S101G-S103A-V104I-A232V-Q245R-N248D、S101G-S103A-V104I-G159D-A232V-Q245R、S101G-S103A-V104I-G159D-A232V-Q245R-N248R、S101G-S103A-V104I-V150L-A232V-Q245R、S103A-A232V、S103A-A232V-H249R、S103A-A232V-Q245R、S103A-V104I-Q245R、S103N-H120F-Y167W-I198L-L233C、T022W-A194F-T213A-L233C-N238L、T022W-E089I-S216F、T033S-A048T、T033S-P086W-S156L-Y209A、T033S-P239T、T033S-T253A、T057R-N183D-Q236N、T143A-Y209A、V004E-T033S-S078R、V004R-S009A-T022R-S078R-S212F、Y209A-K235F、N043R-N076D-H249R、N018R-R045T、G020R-N076D-A230E-S242R、G020R-S024R-N043D-R045T、S024R-N043D-N076D-S242R-H249R、G020R-R045T-H249R、N043R-N076D-S153A-H249R、N043R-N076D-A230E-H249R、N018R-N043D-N076D-H249R、G020R-N043R-N076D-V227I、L111I-A215F-P239S、S024R-N116A-R186K-L233C-Q236N、G023A-S103N-S106G-S212M-A215F、Y209A-N243F、S024R-T033S-P129H-N184D-T253M、S024R-A085V-P086W-G118R-K235F、S024R-A272P、S024R-R269C、G020R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N043D-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-H249R、N018R-N076D-V104I、N018R-G020R-N043D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-G020R-T022W-S024R-N076D-N183D-G211Q-H249R、N018R-S024R-N076D-S101A-N183D-I198L-G211Q-A215F-H249R、S101G-V104I、N018R-T022W-S024R-N076D-N116A-N183D-I198L-G211Q-T213A-A215F-H249R、N018R-G020R-S024R-N076D-S101A-N183D-G211Q-T213A-A215F-H249R、N018R-G020R-S024R-N076D-N116A-N183D-A215F-H249R-N263D、N018R-T022W-S024R-N076D-S101A-N183D-H249R、N018R-S024R-N076D-S101A-N116A-N183D-I198L-A215F-H249R、N018R-T022W-S024R-N076D-N116A-I198L-A215F-H249R-R269H、N018R-N043D-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-S024R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、S078R-S101G-S103A-V104I-L217E-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-S101A-N183D-I198L-T213A-A215F-H249R、N018R-G020R-S024R-N076D-N183D-I198L-T213A-H249R、N018R-G020R-T022W-S024R-N076D-N116A-I198L-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-G211Q-H249R、N018R-G020R-T022W-S024R-N076D-S101A-I198L-G211Q-T213A-H249R、N018R-G020R-T022W-S024R-N076D-H249R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-I198L-G211Q-T213A-A215F-A232V-Q245R、V104I-A232V、N018R-G020R-T022W-S024R-N076D-S101A-N116A-N183D-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N183D-T213A-A215F-H249
R、N018R-T022W-S024R-N076D-S101A-N183D-I198L-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N183D-I198L-H249R、N043D-R045T-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-G020R-S024R-N076D-S101A-N183D-I198L-G211Q-H249R、N018R-G020R-N043R-S101G-S103A-V104I-L217E-A232V-Q245R、S024R-N043R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N043R-R045T-N076D-S078R-S101G-S103A-V104I-Y166F-A176P-A179V-N184T-A187P-A194P、N018R-T022W-S024R-D041E-N076D-S101A-S160T-N183D-G211Q-T213A-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-I198L-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-I198L-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-T213A-H249R、N018R-G020R-S024R-N076D-I198L-T213A-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-I198L-G211Q-H249R、N018R-G020R-S024R-N076D-N183D-G211Q-A215F-H249R、S024R-N076D-V104I、N018R-N076D-S101G-A232V、N018R-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-A215F-H249R、N018R-S024R-L031F-N076D-N116A-N183D-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N116A-N183D-I198L-T213A-H249R-N269S、N018R-G020R-S024R-N076D-S101A-N116A-I198L-A215F-H249R、N018R-N043R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-G020R-S024R-N076D-S101A-N114T-I198L-G211Q-A215F-H249R、S024R-N043R-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、S024R-N076D-S103A-V104I-A232V、N018R-G020R-T022W-S024R-N076D-S101A-I198L-G211Q-A215F-H249R、S101G-V104I-A232V、N018R-T022W-S024R-N076D-N183D-I198L-T213A-A215F-H249R、N018R-T022W-S024R-N076D-N183D-I198L-G211Q-H249R、N018R-G020R-S024R-N076D-N183D-T213A-H249R、N018R-S024R-N076D-S101A-N183D-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N116A-G211Q-T213A-H249R、N018R-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-G211Q-A215F-H249R-T260A、N076D-H249R、N018R-T022W-S024R-N076D-N183D-G211Q-A215F-H249R、N018R-G020R-S024R-N076D-N116A-G211Q-A215F-H249R、N018R-G020R-S024R-N076D-T213A-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-I198L-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N183D-H249R、N076D-V104I-H249R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-G211Q-T213A-A215F-A232V-Q245R、S024R-N043R-R045T-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-N183D-I198L-A215F-H249R、N018R-N076D-S101G-S103A、G020R-S024R-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-G211Q-H249R、S101G-S103A-A232V、S024R-N076D-S101G-A232V、N018R-T022W-S024R-N076D-S101A-N183D-I198L-G211Q-H249R、N018R-G020R-S024R-N076D-S101A-N183D-I198L-G211Q-A215F-H249R、N018R-G020R-S024R-N076D-N183D-I198L-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-H249R、N018R-G020R-S024R-N076D-N116A-A156V-N183D-G211Q-A215F-H249R-N269S、R045T-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-G020R-S024R-N076D-S101A-N183D-I198L-H249R、N018R-G020R-T022W-S024R-N076D-I198L-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-I198L-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N116A-H249R、N018R-N076D-S101G、N018R-S024R-N076D-N116A-N183D-I198L-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-I198L-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-H249R、N018R-N076D-A232V、N018R-G020R-S024R-N076D-S101A-A232V-Q245R、N018R-N043D-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-N183D-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N116A-G211Q-T213A-N237D-H249R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-G211Q-H249R-R275S、N018R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-T213A-A215F-H249R、S024R-N076D、N018R-S024R-N076D-N183D-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-N116A-N183D-I198L-T213A-A215F-H249R、N076D-V104I-A232V-H249R、N018R-N076D-S103A-A232V、N018R-G020R-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-T213A-H249R、N018R-G020R-S024R-N076D-S101A-N183D-T213A-H249R、N018R-G020R-S024R-N076D-S101A-D175E-N183D-G211Q-A215F-H249R、N018R-G020R-N043D-S078R-S101G-S103A-V104I-L217E-A232V-Q245R-A273E、G020R-S024R-N043D-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、P005S-S101G-S103A-V104I-A232V-Q245R-H249R、S103A-V104I-A232V、N018R-G020R-S024R-V068A-N076D-S101A-N116A-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-I198L-A215F-H249R-R275S、N018R-S024R-N076D-N183D-I198L-G211Q-T213A-H249R、N043D-R045T-S101G-S103A-V104I-A232V-Q245R、N018R-S024R-N076D-L217E-S242R-H249R、N076D-S087D-S101G-S103A-V104I-A232V-Q245R、S087D-S101G-S103A-V104I-A232V-Q245R、及びS101G-S103A-V104I-V150L-A232V-S242R-Q245Rから選択されるアミノ酸置換の組みを含むアミノ酸配列からなり、このプロテアーゼ変異体の合計正味電荷は、バチルス・レンタスのサブチリシンGG36プロテアーゼの合計正味電荷と比較して0、+1、+2、+3、+4、+5、-1、-2、-3、-4、又は-5であり、合計正味電荷が:N43D、R45T、N62E、N76D、S101D、P129E、A158E、G159D、G159E、S166D、S188D、A230E、N18R、G20K、G20R、T22R、S24R、N43R、G118R、Q245R、H249R、N269R、E271F、及びE271Lから選択された1箇所以上の置換により得られ、プロテアーゼ変異体のアミノ酸位置は、ププロテアーゼ変異体のアミノ酸配列を配列番号1で示されるバチルス・アミロリケファシエンスのサブチリシンBPN’のアミノ酸配列と整列させることで決定される、バチルス・アミロリケファシエンスのサブチリシンBPN’の対応するアミノ酸位置に割り振られた番号に従って番号付けされる。
(a)N062E、S101D、P129E、A158E、G159D/E、S166D、及び/又はS188Dからなる群から選択される1つ以上の電荷変化を含み;
(b)配列番号1の酵素に対して0、-1、-2、-3、-4又は-5、好ましくは0、-1、-2又は-3、最も好ましくは-1又は-2の電荷を有し;並びに
(c)所望の正味電荷を達成するG20K、S024R、G118R、Q245R、H249R及び/又はE271F/Lからなる群から選択された1、2又は3箇所以上の変異を含む。
(a)N018R、G020K/R、T022R、S024R、N043R、Q245R、H249R及び/又はN269Rからなる群から選択される1つ又は2つ以上の電荷変化を含み;
(b)配列番号1の酵素に対して0、+1、+2、+3、+4又は+5、好ましくは+1、+2又は+3、最も好ましくは+2の電荷を有し;並びに
(c)所望の正味電荷を達成するためにN043D、R045T、N076D及び/又はA230Eからなる群から選択される変異を含む。
本発明は、単離されたプロテアーゼ変異体、非天然に生じるプロテアーゼ変異体、又は組み換えプロテアーゼ変異体(本明細書では「ポリヌクレオチド」とも呼ばれる)を提供する。これらのプロテアーゼ変異体は、総じて本発明のポリペプチドをコードする「本発明の核酸」又は「本発明のポリヌクレオチド」として呼ばれる。以下に記載のすべてのものを包含する本発明の核酸は、本発明のポリペプチドの組み換え体を生産(例えば、発現)するのに、典型的には、対象とするポリペプチドをコードする配列又はそれらの断片を含むプラスミド発現ベクターによる発現を介して生産するのに有用である。上述のように、ポリペプチドには、例えば、酵素活性(例えば、タンパク質分解活性)を有する、変異体サブチリシンのポリペプチドなどの変異体プロテアーゼのポリペプチドが包含され、プロテアーゼ変異体ポリペプチドは、クリーニング用途、及びクリーニングする必要のある物品又は表面(例えば、物品の表面)をクリーニングするためのクリーニング組成物に有用である。
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、X018R-X022W-X024R-X076D-X101A-X183D-X198L-X249R、X043D-X045T-X101G-X103A-X104I-X232V-X245R-X269R、X018R-X020R-X024R-X076D-X101A-X183D-X198L-X211Q-X249R、X018R-X020R-X043R-X101G-X103A-X104I-X217E-X232V-X245R、X024R-X043R-X076D-X078R-X101G-X103A-X104I-X232V-X245R-X269R、X043R-X045T-X076D-X078R-X101G-X103A-X104I-X166F-X176P-X179V-X184T-X187P-X194P、X018R-X022W-X024R-X041E-X076D-X101A-X160T-X183D-X211Q-X213A-X249R、X018R-X020R-X022W-X024R-X076D-X116A-X183D-X198L-X211Q-X215F-X249R、X018R-X020R-X022W-X024R-X076D-X101A-X116A-X198L-X213A-X249R、X018R-X022W-X024R-X076D-X101A-X116A-X183D-X198L-X211Q-X213A-X249R、X018R-X020R-X024R-X076D-X198L-X213A-X249R、X018R-X020R-X022W-X024R-X076D-X116A-X183D-X198L-X211Q-X249R、X018R-X020R-X024R-X076D-X183D-X211Q-X215F-X249R、X024R-X076D-X104I、X018R-X076D-X101G-X232V、X018R-X024R-X076D-X101A-X116A-X183D-X198L-X211Q-X213A-X215F-X249R、X018R-X020R-X022W-X024R-X076D-X116A-X183D-X215F-X249R、X018R-X024R-X031F-X076D-X116A-X183D-X211Q-X213A-X215F-X249R、X018R-X024R-X076D-X101A-X116A-X183D-X198L-X213A-X249R-X269S、X018R-X020R-X024R-X076D-X101A-X116A-X198L-X215F-X249R、X018R-X043R-X076D-X078R-X101G-X103A-X104I-X232V-X245R-X269R、X018R-X020R-X024R-X076D-X101A-X114T-X198L-X211Q-X215F-X249R、X024R-X043R-X078R-X101G-X103A-X104I-X217E-X232V-X245R、X024R-X076D-X103A-X104I-X232V、X018R-X020R-X022W-X024R-X076D-X101A-X198L-X211Q-X215F-X249R、X101G-X104I-X232V、X018R-X022W-X024R-X076D-X183D-X198L-X213A-X215F-X249R、X018R-X022W-X024R-X076D-X183D-X198L-X211Q-X249R、X018R-X020R-X024R-X076D-X183D-X213A-X249R、X018R-X024R-X076D-X101A-X183D-X211Q-X215F-X249R、X018R-X020R-X022W-X024R-X076D-X116A-X211Q-X213A-X249R、X018R-X078R-X101G-X103A-X104I-X232V-X245R-X269R、X018R-X022W-X024R-X076D-X101A-X116A-X183D-X211Q-X215F-X249R-X260A、X076D-X249R、X018R-X022W-X024R-X076D-X183D-X211Q-X215F-X249R、X018R-X020R-X024R-X076D-X116A-X211Q-X215F-X249R、X018R-X020R-X024R-X076D-X213A-X249R、X018R-X020R-X022W-X024R-X076D-X116A-X183D-X198L-X249R、X018R-X020R-X022W-X024R-X076D-X101A-X183D-X249R、X076D-X104I-X249R、X020R-X022W-X101A-X103A-X104I-X116A-X183D-X211Q-X213A-X215F-X232V-X245R、X024R-X043R-X045T-X078R-X101G-X103A-X104I-X217E-X232V-X245R、X018R-X020R-X022W-X024R-X076D-X183D-X198L-X215F-X249R、X018R-X076D-X101G-X103A、X020R-X024R-X101G-X103A-X104I-X232V-X245R-X269R、X018R-X020R-X024R-X076D-X101A-X116A-X183D-X211Q-X249R、X101G-X103A-X232V、X024R-X076D-X101G-X232V、X018R-X022W-X024R-X076D-X101A-X183D-X198L-X211Q-X249R、X018R-X020R-X024R-X076D-X101A-X183D-X198L-X211Q-X215F-X249R、X018R-X020R-X024R-X076D-X183D-X198L-X249R、X018R-X022W-X024R-X076D-X101A-X116A-X183D-X198L-X211Q-X249R、X018R-X020R-X024R-X076D-X116A-X156V-X183D-X211Q-X215F-X249R-X269S、X045T-X076D-X101G-X103A-X104I-X232V-X245R-X249R、X018R-X020R-X024R-X076D-X101A-X183D-X198L-X249R、X018R-X020R-X022W-X024R-X076D-X198L-X211Q-X215F-X249R、X018R-X020R-X022W-X024R-X076D-X101A-X116A-X198L-X211Q-X215F-X249R、X018R-X020R-X022W-X024R-X076D-X116A-X249R、X018R-X076D-X101G、X018R-X024R-X076D-X116A-X183D-X198L-X213A-X215F-X249R、X018R-X020R-X022W-X024R-X076D-X101A-X116A-X198L-X213A-X215F-X249R、X018R-X024R-X076D-X101A-X116A-X183D-X198L-X211Q-X249R、X018R-X076D-X232V、X018R-X020R-X024R-X076D-X101A-X232V-X245R、X018R-X043D-X045T-X076D-X101G-X103A-X104I-X232V-X245R、X018R-X022W-X024R-X076D-X183D-X213A-X215F-X249R、X018R-X024R-X076D-X101A-X116A-X211Q-X213A-X237D-X249R、X018R-X020R-X024R-X076D-X101A-X116A-X183D-X211Q-X249R-X275S、X018R-X022W-X024R-X076D-X101A-X116A-X183D-X198L-X211Q-X213A-X215F-X249R、X024R-X076D、X018R-X024R-X076D-X183D-X211Q-X215F-X249R、X018R-X022W-X024R-X076D-X116A-X183D-X198L-X213A-X215F-X249R、X076D-X104I-X232V-X249R、X018R-X076D-X103A-X232V、X018R-X020R-X024R-X076D-X101A-X116A-X183D-X198L-X211Q-X213A-X249R、X018R-X020R-X024R-X076D-X101A-X183D-X213A-X249R、X018R-X020R-X024R-X076D-X101A-X175E-X183D-X211Q-X215F-X249R、X018R-X020R-X043D-X078R-X101G-X103A-X104I-X217E-X232V-X245R-X273E、X020R-X024R-X043D-X045T-X076D-X101G-X103A-X104I-X232V-X245R、X005S-X101G-X103A-X104I-X232V-X245R-X249R、X103A-X104I-X232V、X018R-X020R-X024R-X068A-X076D-X101A-X116A-X213A-X215F-X249R、X018R-X022W-X024R-X076D-X101A-X198L-X215F-X249R-X275S、X018R-X024R-X076D-X183D-X198L-X211Q-X213A-X249R、及びX043D-X045T-X101G-X103A-X104I-X232V-X245Rから選択されるアミノ酸置換の組み合わせを含むアミノ酸配列からなり、このサブチリシン変異体のアミノ酸位置は、配列番号1で示されるB.アミロリケファシエンスのサブチリシンBPN’のアミノ酸配列と対応させて番号付けされる、核酸を提供する。
R、S101G-S103A-V104I-P129E-G159E-A232V-N238R-Q245R-N248D、S101G-S103A-V104I-A158E-G159E-S188D-A232V-N238R-Q245R-N248D、S024R-S101G-S103A-V104I-A232V-Q245R-N248D-H249R、T022A-S024R-S101G-S103A-V104I-P129E-L148I-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-A158E-A232V-N238R-Q245R-N248D、S101G-S103A-V104I-S128N-P129E-A232V-N238R-Q245R-N248D、T022A-S101G-S103A-V104I-S128N-G159E-A232V-Q245R-N248D、T022A-S101G-S103A-V104I-S128N-P129E-A158E-A232V-N238R-Q245R-N248D、S101G-S103A-V104I-S128N-P129E-S188D-A232V-Q245R-N248D-H249R、T022A-S024R-S101G-S103A-V104I-S128N-P129E-A158E-S188D-A232V-Q245R-N248D-H249R、S024R-S101G-S103A-V104I-S128N-A158E-G159E-S188D-A232V-Q245R-N248D、T022A-S024K-S101G-S103A-V104I-S128N-A158E-G159E-A232V-Q245R-N248D、S101G-S103A-V104I-P129E-L148I-S188D-A232V-Q245R-N248D、S024R-S101G-S103A-V104I-L148I-A232V-Q245R-N248D、T022A-S101G-S103A-V104I-L148I-S188D-A232V-Q245R-N248D、S024R-S101G-S103A-V104I-S128N-P129E-S188D-A232V-Q245R-N248D、S101G-S103A-V104I-S128N-P129E-A158E-A232V-N238R-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-P129E-L148I-A158E-S188D-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-L148I-A158E-S188D-A232V-Q245R-N248D、S101G-S103A-V104I-L148I-G159E-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-A158E-S188D-A232V-Q245R-N248D、及びS101G-S103A-V104I-S128N-P129E-A158E-A232V-Q245R-N248D-H249Rから選択されるアミノ酸置換の組み合わせを含むアミノ酸配列からなり、このサブチリシン変異体のアミノ酸位置は、配列番号1で示されるB.アミロリケファシエンスのサブチリシンBPN’のアミノ酸配列と対応させて番号付けされる、核酸を提供する。
R、G020R-S101G-I198L-A215F-A232V-Q245R、N018R-S024R-N076D-T213A-A215F-H249R、G020R-S078R-S101G-S103A-V104I-N116A-G211Q-A232V-Q245R、G020R-T022W-S078R-S101A-S103A-V104I-N116A-N183D-A215F-A232V-Q245R、G020R-T022W-S078R-S101A-S103A-V104I-N116A-N183D-T213A-A232V-Q245R、S024R-A232V-Q245R、N018R-S024R-N043D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-S024R-N076D-S101A-A215F-H249R、N018R-T022W-S024R-N076D-N116A-T213A-H249R、S101G-S103A-V104I-A232V-Q245R、N018R-S024R-N076D-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-N116A-T213A-A215F-H249R、N043D-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N043D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、G020R-T022W-S078R-S101G-S103A-V104I-N116A-N183D-G211Q-A232V-Q245R、N018R-S024R-N076D-S101A-I198L-G211Q-A215V-H249R、N018R-T022W-S024R-N076D-N116A-G211Q-H249R、G020R-S103A-V104I-A232V-Q245R、G020R-T22W-S101A-S103A-V104I-G211Q-A215F-A232V-Q245R、S024R-N076D-S101G-S103A-V104I-A232V-Q245R、G020R-S101G-S103A-V104I-N116A-A232V-Q245R、N018R-T22W-S024R-N076D-I198L-A215F-H249R、G020R-T022W-S103A-V104I-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-G211Q-T213A-A232V-Q245R、G020R-T022W-S101G-S103A-V104I-G211Q-T213A-A215F-A232V-Q245R、N018R-N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-S101A-I198L-T213A-A215F-H249R、N018R-T22W-S024R-N076D-S101A-A215F-H249R、G020R-R045T-S101G-S103A-V104I-A232V-Q245R、G020R-S078R-S101G-S103A-V104I-T180A-A232V-Q245R、G020R-T022W-S078R-S101G-S103A-V104I-N116A-N183D-A215F-A232V-Q245R、N018R-S101G-S103A-V104I、G020R-T22W-S101A-S103A-V104I-N116A-G211Q-T213A-A215F-A232V-Q245R、N018R-S024R-N076D-S103A-A232V-Q245R、G020R-S078R-S101A-S103A-V104I-N116A-N183D-A232V-Q245R、N018R-S024R-N076D-G211Q-H249R、G020R-S101A-S103A-V104I-T213A-A215F-A232V-Q245R、N018R-G020R-N043D-S101G-S103A-V104I-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-G211Q-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-N116A-G211Q-A215F-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-N116A-G211Q-A232V-Q245R、N018R-S024R-N076D-A232V-H249R、N018R-S024R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-N076D-Q245R、S024R-V104I-Q245R、S101G-A232V、G020R-T22W-S101A-S103A-V104I-N116A-G211Q-A215F-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-I198L-T213A-H249R、G020R-T022W-S078R-S101A-S103A-V104I-A232V-Q245R、G020R-T022W-S078R-S101A-S103A-V104I-I198L-A232V-Q245R、S024R-Q245R-H249R、G020R-S101G-S103A-V104I-N116A-G211Q-A232V-Q245R、N018R-T22W-S024R-N076D-N116A-G211Q-H249R、S024R-S101G-V104I-H249R、N018R-S024R-N076D-N116A-I198L-G211Q-T213A-A215F-H249R、N018R-S024R-V104I、G020R-T022W-S078R-S101A-S103A-V104I-N183D-I198L-T213A-A215F-A232V-Q245R、N018R-G020R-T22W-S024R-N076D-N116A-N183D-I198L-T213A-H249R、G020R-T022W-S101A-S103A-V104I-A232V-Q245R、Q012H-G020R-S078R-S101G-S103A-V104I-I198L-G211Q-T213A-A232V-Q245R、N018R-S024R-N076D-S101A-G211Q-A215F-H249R、N018R-S024R-N076D-T213A-H249R、S024R-V104I-H249R、N018R-T022W-S024R-N076D-G211Q-H249R、N018R-N076D-S103A-V104I-H249R、N043R-N076D-S101G-S103A-V104I-L217E-A232V-Q245R、G020R-S078R-S101G-S103A-V104I-N183D-G211Q-T213A-A232V-Q245R-E271G、N018R-T022W-S024R-N076D-S101A-N116A-I198L-A215F-H249R、N018R-S024R-N043D-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-S024R-N076D-S101A-I198L-A215F-H249R、N018R-T022W-S024R-N076D-N116A-I198L-G211Q-T213A-H249R、N018R-S024R-N076D-S101A-N116A-T213A-A215F-H249R、G020R-N043D-R045T-S078R-S101G-S103A-V104I-A232V-Q245R、R045T-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-T22W-S024R-N076D-S101A-N116A-A215F-H249R、N043D-S101G-S103A-V104I-A232V-Q245R-N269R、G020R-T022W-S078R-S101A-S103A-V104I-N116A-N183D-T213A-A215F-A232V-Q245R、N018R-S024R-N076D-N116A-G211Q-T213A-A215F-H249R、S024R-S103A-M175L-A232V-H249R、N018R-S024R-N076D-N116A-T213A-H249R、G020R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、G020R-S078R-S101A-S103A-V104I-N116A-N183D-G211Q-T213A-A215F-A232V-Q245R、S024R-N043R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-S024R-N076D-S101A-N116A-I198L-T213A-A215F-H249R、N043R-R045T-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-S101A-I198L-G211Q-Q245R、G020R-S024R-N043D-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、S024R-A232V、G020R-S078R-S101A-S103A-V104I-N116A-N183D-G211Q-A232V-Q245R、S024R-N076D-S101G-A232V-Q245R、N018R-N076D-S101G-S103A-V104I-H249R、N018R-S024R-N076D-I198M-G211Q-T213A-A215F-H249R、N018R-T22W-S024R-N076D-S101A-I198L-A215F-H249R、N018R-N043R-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、G020R-T022W-S103A-G211Q-T213A-A215F-A232V-Q245R、G020R-S078R-S101A-S103A-V104I-N116A-N183D-G211Q-T213A-A232V-Q245R、R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-T22W-S024R-N076D-S101A-G211Q-T213A-H249R、N018R-S024R-N076D-N116A-I198L-A215F-H249R-V268G、N018R-T022W-S024R-N076D-S101A-G211Q-H249R、N018R-T022W-S024R-N076D-S101A-N116A-I198L-G211Q-H249R、S101G-S103A-V104I-Q245R、N018R-N076D-S101G-A232V-Q245R、N018R-G020R-R045T-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-S101A-N116A-I198L-H249R、N018R-T022W-S024R-N076D-N116A-I198L-T213A-H249R、S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、G020R-N043R-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-N043D-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、R045T-S101G-S103A-V104I-A232V-Q245R-N269R、S024R-S103A-A232V、N018R-S024R-N076D-S101A
-G211Q-H249R、N043D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-N043R-R045T-N076D-S076T-S101G-S103A-V104I-A232V-Q245R-A273T、N018R-G020R-N043D-S078R-S101G-S103A-V104I-A232V-Q245R、G020R-S078R-S101A-S103A-V104I-N183D-A215F-A232V-Q245R、N018R-S024R-N076D-S101G-A232V、A232V-Q245R、N043R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-V234I-Q245R、S024R-N076D-S103A-V104I-Q245R、G020R-S078R-S101A-S103A-V104I-G211Q-T213A-A232V-Q245R、N043D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R-A272V、N018R-G020R-S024R-N076D-N116A-N183D-I198L-G211Q-H249R、N018R-S103A-V104I-A232V、G020R-T022W-S101G-S103A-V104I-N116A-N183D-T213A-A215F-A232V-Q245R、S024R-N043R-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-T022W-S024R-N076D-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N116A-I198L-G211Q-T213A-H249R、G020R-T22W-S078R-S101A-S103A-V104I-N116A-N183D-T213A-A232V-Q245R、G020R-T022W-S078R-S101G-S103A-V104I-G211Q-T213A-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-A215F-A232V-Q245R、N018R-G020R-S024R-N076D-N116A-N183D-A215F-H249R、N018R-S024R-N076D-N116A-M117I-N183D-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N116A-I198L-T213A-H249R、N018R-T22W-S024R-N076D-S101A-I198L-T213A-A215F-H249R、N018R-N043D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-I198L-A232V-Q245R、N018R-N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-S024R-N076D-N116A-I198L-Y209H-T213A-H249R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-G211Q-T213A-A232V-Q245R、S024R-N076D-S101G-M175L-A232V-Q245R、N018R-N043D-R045T-S101G-S103A-V104I-A232V-Q245R、R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、G020R-S078R-S101A-S103A-V104I-N116A-N183D-I198L-A215F-A232V-Q245R、N043R-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-S024R-N076D-I198L-T213A-A215F-H249R、N018R-T022W-S024R-N076D-I198L-A215F-H249R、N018R-T022W-S024R-N076D-N116A-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-I198L-T213A-A215F-H249R、N018R-T022W-S024R-N076D-N116A-G211Q-T213A-H249R、N018R-S024R-Q245R、N018R-T022W-S024R-N076D-S101A-N116A-A215F-H249R、S024R-N076D-V104I-Q245R、K027R-N043R-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-S024R-N076D-N116A-I198L-G211Q-T213A-H249R、N018R-S024R-N076D-N116A-I198L-H249R、N018R-S024R-N076D-N183D-I198L-G211Q-T213A-A215F-H249R、G020R-T022W-S101A-S103A-V104I-N116A-G211Q-T213A-A215F-A232V-Q245R、N018R-N043D-R045T-S078R-S101G-S103A-V104I-A232V-Q245R、N043R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-T22W-S024R-N076D-N116A-T213A-A215F-H249R、N018R-T022W-S024R-N076D-N116A-G211Q-A215F-H249R、G020R-S078R-S101G-S103A-V104I-N116A-N183D-T213A-A232V-Q245R、N018R-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-S101G-V104I、G020R-S078R-S101G-S103A-V104I-N116A-N183D-G211Q-T213A-A215F-A232V-Q245R、G020R-S078R-S101A-S103A-V104I-A232V-Q245R、N018R-S024R-N076D-S101A-I198L-G211Q-H249R、N018R-S024R-N076D-I198L-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N116A-I198L-G211Q-T213A-H249R、N018R-N076D-H249R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-I198L-H249R、N018R-S024R-N076D-S101A-N116A-G211Q-T213A-H249R、G020R-T022W-S078R-S101A-S103A-V104I-N116A-N183D-G211Q-T213A-A215F-A232V-Q245R、G020R-T022W-S101G-S103A-V104I-A114T-T213A-A215F-A232V-Q245R、N018R-T22W-S024R-N076D-N116A-G211Q-T213A-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-N183D-H249R、G020R-S101A-S103A-V104I-N116A-N183D-T213A-A232V-Q245R、N018R-T022W-S024R-N076D-S101A-G211Q-T213A-H249R、N018R-T022K-N043D-S101G-S103A-V104I-A232V-Q245R、N018R-S101G-S103A-V104I-A232V-Q245R-N269R、G020R-S078R-S101G-S103A-V104I-N116A-N183D-G211Q-T213A-A215F-A232V、N018R-S024R-N076D-N116A-H249R、G020R-S024R-N076D-S101G-S103A-V104I-A232V-Q245R、N043D-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-S024R-N076D-S101A-N116A-I198L-G211Q-H249R、N018R-T022W-S024R-N076D-I198L-T213A-A215F-H249R、N018R-N043D-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、G020R-T22W-S101G-S103A-V104I-N116A-N183D-T213A-A215F-A232V-Q245R、G020R-S101G-S103A-V104I-N183D-G211Q-A232V-Q245R-、N018R-S024R-N076D-S101A-I198L-T213A-H249R、N018R-S024R-N076D-S101A-I198L-H249R、N018R-S024R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-S024R-N076D-S101A-N183D-T213A-H249R、N018R-N043D-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、G020R-S078R-S101G-S103A-V104I-N116A-A131V-N183D-T213A-A232V-Q245R、N018R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-S024R-N076D-S101A-N183D-G211Q-H249R、N076D-S101G-S103A-V104I-A232V-Q245R-H249R、S024R-S101G-Q245R、S024R-N076D-S101G-Q245R、N076D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-G020R-S024R-N076D-S101A-N183D-G211Q-A215F-H249R、S024R-S101G、N018R-T22W-S024R-N076D-T213A-A215F-H249R、G020R-N043D-S101G-S103A-V104I-A232V-Q245R、G020R-T022W-S101G-S103A-V104I-N183D-I198L-T213A-A215F-A232V-Q245R、N018R-N043D-R045T-S101G-S103A-V104I-A232V-Q245R-N269R、N043D-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、S024R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、G020R-T022W-S101A-S103A-V104I-I198L-G211Q-A215F-A232V-Q245R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-A215F-A232V-Q245R、N018R-G020R-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-T022W-S024R-N076D-S101A-A215F-H249R、N018R-V104I、N018R-S024R-N076D-N116A-I198L-A215F-H249R、N018R-S024R-N076D-L088I-S101A-N116A-I198L-G211Q-A215F-H
249R、N018R-T022W-S024R-N076D-S101A-N116A-G211Q-T213A-H249R、N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-N076D-S101G-V104I-H249R、N018R-T022W-S024R-N076D-S101A-T213A-A215F-H249R、N018R-T22W-S024R-N076D-S101A-N116A-I198L-A215F-H249R、N018R-G020R-S101G-S103A-V104I-A232V-Q245R-H249R、S101G-S103A-V104I-A232V-Q245R-H249R-N269R、S024R-N076D-Q245R、N018R-G020R-N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-S024R-N076D-A215F-H249R、N018R-S024R-N076D-S101A-N116A-N183D-I198L-T213A-H249R、N018R-G020R-S024R-N076D-G211Q-A215F-H249R、N043D-S101G-S103A-V104I-A232V-Q245R、G020R-T22W-S078R-S101A-S103A-V104I-N116A-N183D-A215F-A232V-Q245R、N018R-S024R-N076D-I198L-G211Q-A215F-H249R、N043R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N043R-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、G020R-N043D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-T022W-S024R-N076D-S101A-T213A-H249R、G020R-T022W-S101A-N116A-I198L-G211Q-T213A-A215F-H249R、N043R-R045T-S078R-S101G-S103A-V104I-N218S-A232V-Q245R、N018R-S103A、G020R-T22W-S101G-S103A-V104I-N116A-N183D-A215F-A232V-Q245R、N018R-S024R-N076D-S101A-H249R、N018R-T022W-S024R-N076D-G211Q-T213A-H249R、S024R-N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-A232V-Q245R、G020R-S101A-S103A-V104I-N116A-N183D-G211Q-T213A-A215F-A232V-Q245R、K027R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、G020R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-G020R-S024R-N076D-N116A-N183D-T213A-A215F-H249R、N018R-S024R-N076D-V104I、S101G-S103A-V104I-A232V-H249R、N018R-S024R-N076D-N116A-N183D-G211Q-H249R、N018R-G020R-S024R-N076D-N116A-A215F-H249R、N018R-S024R-N076D-N183D-T213A-A215F-H249R、N018R-T022W-S024R-N076D-I198L-G211Q-H249R、N043D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R-R275S、G020R-T022W-S101A-S103A-V104I-N116A-N183D-G211Q-A232V-Q245R、N018R-T022W-S024R-N076D-S101A-I198L-G211Q-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-I198L-G211Q-T213A-A215F-H249R、N018R-G020R-S024R-N076D-N183D-H249R、N018R-S024R-N076D-N116A-I198L-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N116A-G211Q-H249R、V004M-N018R-S024R-N076D-N116A-I198L-G211Q-T213A-H249R、V104I-A232V-H249R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-G211Q-A215F-A232V-Q245R、G020R-S101A-S103A-V104I-N116A-N183D-G211Q-A232V-Q245R-T274I、G020R-S101A-S103A-V104I-T213A-A232V-Q245R、G020R-S101G-S103A-V104I-N116A-N183D-G211Q-T213A-A232V-Q245R、G020R-S024R-N043D-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-S024R-N076D-S103A-H249R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-G211Q-A215F-H249R、N018R-G020R-S024R-N076D-N116A-N183D-I198L-H249R、N018R-T022W-S024R-N076D-N116A-I198L-A215F-H249R、N018R-S024R-N076D-S101A-G211Q-T213A-A215F-H249R-A270V、N018R-N043D-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、G020R-T022W-S101G-S103A-V104I-N183D-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-T213A-H249R、N018R-T022W-S024R-N076D-I198L-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-I198L-T213A-H249R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-A232V-Q245R、N018R-T22W-S024R-N076D-N116A-I198L-T213A-H249R、N043R-R045T-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-S024R-N076D-S101G-S103A-V104I-A232V、S101G-H249R、S024R-N076D-S101G-S103A-V104I-M175L-H249R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-A232V-Q245R-N269S、N018R-S024R-N076D-S101A-N116A-I198L-H249R、N018R-T022W-S024R-N076D-N116A-H249R、N018R-G020R-S024R-N076D-S101A-N183D-I198L-A215F-H249R、N018R-S024R-N076D-T213A-A215F-H249R-T260K、N018R-S024R-N076D-N116A-G211Q-T213A-H249R、N018R-G020R-T022W-S024R-N076D-N116A-I198L-H249R、S024R-N076D-S101G-S103A-V104I-Q245R、S024R-N076D-S103A-H249R、N018R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-S024R-N076D-I198L-G211Q-H249R、N018R-T022W-S024R-N076D-S101A-I198L-G211Q-T213A-H249R、G020R-S024R-R045T-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-S024R-N076D-N183D-G211Q-T213A-H249R、N018R-N043D-R045T-S078R-S101G-S103A-V104I-A232V-Q245R-A272D、N018R-S024R-N076D-N116A-I198L-T213A-A215F-H249R、N018R-T22W-S024R-N076D-S101A-I198L-H249R、N018R-T022W-S024R-N076D-N116A-I198L-H249R、S024R-N076D-S101G-S103A-A232V、S024R-S103A-V104I、N018R-S024R-N076D-S101A-N116A-N183D-G211Q-A215F-H249R、S024R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、G020R-S101G-S103A-V104I-N116A-N183D-A232V-Q245R、S024R-N043D-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、G020R-T022W-S101A-S103A-V104I-N183D-G211Q-T213A-A215F-A232V-Q245R、G020R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-S024R-N076D-S101A-N116A-I198L-G211Q-A215F-H249R、G020R-S101A-S103A-V104I-N116A-N183D-A215F-A232V-Q245R、N018R-N043R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-S024R-N076D-I198L-T213A-H249R、N018R-S024R-N076D-N116A-N183D-T213A-H249R、G020R-N043D-S101G-S103A-V104I-A232V-Q245R-N269R、S024R-N076D-S103A-Q245R、N018R-T022W-S024R-N076D-S101A-N116A-G211Q-T213A-A215F-H249R、S103A-V104I-Q245R、N018R-T022W-S024R-N076D-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-N116A-N183D-I198L-H249R、N018R-T022W-S024R-N076D-I198L-G211Q-T213A-H249R、N018R-S024R-N076D-N116A-N183D-G211Q-T213A-A215F-H249R、N018R-G020R-N043D-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-G0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2W-S024R-N076D-N116A-A215F-H249R、N043R-N076D-S101G-S103T-V104I-A232V-Q245R-H249R-N269R、G020R-S078R-S101A-S103A-V104I-G115E-N116A-N183D-G211Q-T213A-A232V-Q245R、N018R-S024R-N076D-I198L-H249R、N018R-S024R-N076D-S101A-N116A-N183D-H249R、G020R-S101G-S103A-V104I-N116A-N183D-G211Q-A232V-Q245R、N018R-S024R-N076D-S101G、N076D-S101G-A232V-Q245R、N018R-N076D-S101G-S103A-V104I-Q245R、N018R-R045T-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-S024R-N076D-A215F-H249R、N018R-V104I-A232V、N043D-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、S024R-N076D-S101G-A232V-H249R、S103A-A232V-Q245R、G020R-S101G-S103A-V104I-N116A-N183D-G211Q-T213A-A215F-A232V-Q245R、N018R-G020R-S024R-N076D-N116A-N183D-I198L-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-S101A-I198L-G211Q-A215F-H249R、S024R-N076D-S103A-V104I-H249R、S024R-S101G-S103A-V104I、G020R-S101G-S103A-V104I-N116A-N183D-G211Q-A215F-A232V-Q245R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-A215F-H249R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-G211Q-T213A-A215F-A232V-Q245R、G020R-S024R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-N116A-N183D-T213A-H249R、N018R-G020R-S024R-N076D-A131T-A215F-H249R、N018R-S024R-N076D-S101A-N116A-N183D-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N116A-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-I198L-A215F-H249R、N018R-T022W-S024R-N076D-N183D-G211Q-H249R、N018R-T022W-S024R-N076D-S101A-N116A-T213A-A215F-H249R、N018R-G020R-S024R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N043R-S101G-S103A-V104I-Q245R-H249R、N018R-N076D-A232V-H249R、N018K-N076D-S078R-S101G-S103A-V104I-L217E-A232V-Q245R-N269R、N018R-G020R-S024R-N043D-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-S101A-N116A-T213A-A215F-H249R-L267I、A232V-H249R、N018R-G020R-S024R-N076D-N116A-G211Q-T213A-A215F-H249R、N076D-V104I-Q245R、N018R-G020R-S024R-N076D-N183D-I198L-G211Q-A215F-H249R、N018R-S024R-N076D-S101A-G211Q-T213A-H249R、S024R-S101G-S103A-A232V、N018R-G020R-T022W-S024R-N076D-N116A-N183D-I198L-T213A-A215F-H249R、N018R-G020R-S024R-N076D-N116A-N183D-I198L-G211Q-T213A-H249R、N018R-G020R-T022W-S024R-N076D-S101A-A215F-H249R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-G211Q-A215F-A232V-Q245R、N018R-S024R-N076D-N116A-I198L-G211Q-H249R、S103A-A232V-H249R、N018R-G020R-S024R-N076D-N116A-N183D-I198L-A215F-H249R、N018R-S024R-N076D-N116A-N183D-I198L-T213A-H249R、N018R-T022W-S024R-N076D-N183D-T213A-H249R、N018R-S024R-N076D-S101A-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-G211Q-H249R、N018R-R045T-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-G020R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-N116A-I198L-T213A-A215F-H249R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-G211Q-T213A-A232V-Q245R、N018R-G020R-S024R-N076D-I198L-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-G211Q-H249R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-A232V-Q245R-T274I、S024R-S103A-Q245R-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-H249R、N018R-S024R-N076D-S101A-I198L-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-N116A-I198L-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-T213A-H249R、N018R-N043D-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-T022W-S024R-N076D-N116A-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N183D-I198L-T213A-H249R、N043D-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-S024R-N076D-I198L-G211Q-T213A-A215F-H249R、N018R-G020R-S024R-N076D-N116A-N183D-T213A-H249R、S103A-A232V、N018R-T022W-S024R-N076D-N116A-N183D-A215F-H249R、N018R-S024R-N076D-S101A-N116A-H249R、N018R-N043R-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-S101A-N183D-G211Q-A215F-H249R、N043R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-I198L-T213A-H249R、N018R-S024R-N076D-N183D-I198L-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N183D-G211Q-H249R、N018R-G020R-S024R-N076D-I198L-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N183D-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-I198L-H249R、N018R-S024R-N076D-N183D-I198L-G211Q-H249R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-T213A-A232V-Q245R、N018R-G020R-S024R-N076D-N116A-N183D-G211Q-T213A-H249R、N018R-S024R-N076D-N116A-N183D-I198L-G211Q-T213A-A215F-H249R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-A215F-A232V-Q245R、N018R-S024R-N076D-S101A-N183D-H249R、N018R-S024R-N076D-A232V、N018R-T022W-S024R-N076D-S101A-N116A-H249R、G020R-S101A-S103A-V104I-N116A-N183D-I198L-G211Q-T213A-A215F-A232V-Q245R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-G211Q-A232V-Q245R-N263S、S024R-N076D-S101G-V104I-A232V-H249R、N043R-S078R-S101G-S103A-V104I-A232V-Q245R、S024R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-S024R-N076D-S101A-N183D-I198L-T213A-A215F-H249R、N018R-G020R-S024R-N076D-I198L-A215F-H249R、N018R-G020R-S024R-N076D-S101A-N116A-T213A-H249R、N018R-S024R-N076D-S101A-V197A-T213A-A215F-H249R、S024R-S101G-S103A、N018R-S024R-N076D-S101A-N116A-G211Q-A215F-H249R、N043R-N076D-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、S024R-V104I-A232V、N018R-S024R-N076D-N183D-G211Q-H249R、G020R-N043R-R045T-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-S101A-N116A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R-N076D-N116A-N183D-I198L-G211Q-H249R、N018R-S024R-N076D-S101G-Q245R、N018R-S024R-N076D-S101A-N116A-N183D-I198L-T213A-A215F-H249R、N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-N116A-I198L-T213A-A215F-H249R、N076D-V104I-A232V-Q245R、K027R-N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-S101A-N183D-T213A-A215F-H249R、N018R-S024R-N076D-S103A-V104I-L135I-A232V、N018R-G020R-T022W-S024R-N076D-N183D-I198L-G211Q-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-A215F-H249R、N018R-S024R-N076D-S101A-N116A-N183D-G211Q-H249R、N018R-T022W-S024R-N076D-N183D-G211Q-T213A-A215F-H249R、N076D-S101G-S103A-V104I-A232V-H249R、P005S-N018R-T022W-S024R-N076D-S101A-T213A-A215F-H249R、N018R-S024R-N076D-N116A-N183D-A215F-H249R、N018R-S024R-N076D-N183D-I198L-A215F-H249R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-H249R、N018R-T022W-S024R-N076D-N116A-N183D-G211Q-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N183D-G211Q-T213A-H249R、N018R-G020R-S024R-N076D-N116A-I198L-H249R、N018R-S024R-N076D-N183D-G211Q-T213A-H249R、N018R-S024R-N076D-S101A-N116A-N183D-T213A-H249R、N018R-S024R-N076D-N116A-N183D-I198L-A215F-H249R、N018R-T022W-S024R-N076D-N183D-I198L-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-N183D-H249R、N018R-T022W-S024R-N076D-S101A-N183D-I198L-A215F-H249R、N018R-G020R-N043D-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-N183D-I198L-A215F-A232V-Q245R、N076D-S101G-S103A-V104I-H249R、N018R-G020R-S024R-N076D-N183D-I198L-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N183D-A215F-H249R、N018R-G020R-S024R-N076D-G211Q-T213A-H249R、N018R-S024R-N076D-N116A-N183D-G211Q-T213A-H249R、N018R-S024R-N076D-N116A-N183D-I198L-H249R、N018R-G020R-S024R-N076D-G211Q-N243D-H249R、N018R-G020R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-T022W-S024R-N076D-N183D-I198L-G211Q-T213A-H249R、N018R-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-N116A-I198L-G211Q-T213A-A215F-H249R、S024R-N076D-S101G、N018R-G020R-S024R-N076D-S101A-I198L-T213A-A215F-H249R、N018R-T022W-S024R-N076D-N116A-N183D-G211Q-T213A-H249R、N018R-G020R-S024R-N076D-N183D-A215F-H249R、N018R-N043D-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-T022W-S024R-N076D-N116A-N183D-G211Q-T213A-Q245R、G020R-S024R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-G020R-R045T-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-S024R-N076D-S101A-N183D-I198L-G211Q-H249R、N018R-T022W-S024R-N076D-N183D-G211Q-T213A-H249R、N018R-G020R-S024R-N076D-N116A-I198L-G211Q-A215F-H249R-N269S、N018R-G020R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-A215F-H249R、G020R-T022W-S101A-S103A-V104I-N183D-T213A-A215F-A232V-Q245R、N018R-S024R-N076D-A086V-S101A-N183D-I198L-G211Q-H249R、N018R-N076D-S101G-I198T-A232V、N018R-G020R-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N183D-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-N183D-H249R-A248T、N018R-N076D-V104I-Q245R-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-A215F-H249R、N018R-T022W-S024R-N076D-N116A-N183D-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-G211Q-T213A-A215F-H249R、N018R-G020R-S024R-N076D-S101A-H249R、N018R-G020R-S024R-N076D-S101A-N116A-T213A-A215F-H249R、N018R-T022W-S024R-N076D-N116A-N183D-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-N116A-N183D-I198L-G211Q-T213A-H249R、N043R-R045T-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、N043R-R045T-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-N076D-S101G-V104I、G020R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N043D-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-H249R、N018R-N076D-V104I、N018R-G020R-N043D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-G020R-T022W-S024R-N076D-N183D-G211Q-H249R、N018R-S024R-N076D-S101A-N183D-I198L-G211Q-A215F-H249R、S101G-V104I、N018R-T022W-S024R-N076D-N116A-N183D-I198L-G211Q-T213A-A215F-H249R、N018R-G020R-S024R-N076D-S101A-N183D-G211Q-T213A-A215F-H249R、N018R-G020R-S024R-N076D-N116A-N183D-A215F-H249R-N263D、N018R-T022W-S024R-N076D-S101A-N183D-H249R、N018R-S024R-N076D-S101A-N116A-N183D-I198L-A215F-H249R、N018R-T022W-S024R-N076D-N116A-I198L-A215F-H249R-R269H、N018R-N043D-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-S024R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、S078R-S101G-S103A-V104I-L217E-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-S101A-N183D-I198L-T213A-A215F-H249R、N018R-G020R-S024R-N076D-N183D-I198L-T213A-H249R、N018R-G020R-T022W-S024R-N076D-N116A-I198L-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-G211Q-H249R、N018R-G020R-T022W-S024R-N076D-S101A-I198L-G211Q-T213A-H249R、N018R-G020R-T022W-S024R-N076D-H249R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-I198L-G211Q-T213A-A215F-A232V-Q245R、V104I-A232V、N018R-G020R-T022W-S024R-N076D-S101A-N116A-N183D-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N183D-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N183D-I198L-G211Q-T213A-H249R、N018R-T022W-S024R-N
076D-S101A-N183D-I198L-H249R、N043D-R045T-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-G020R-S024R-N076D-S101A-N183D-I198L-G211Q-H249R、N018R-G020R-N043R-S101G-S103A-V104I-L217E-A232V-Q245R、S024R-N043R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N043R-R045T-N076D-S078R-S101G-S103A-V104I-Y166F-A176P-A179V-N184T-A187P-A194P、N018R-T022W-S024R-D041E-N076D-S101A-S160T-N183D-G211Q-T213A-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-I198L-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-I198L-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-T213A-H249R、N018R-G020R-S024R-N076D-I198L-T213A-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-I198L-G211Q-H249R、N018R-G020R-S024R-N076D-N183D-G211Q-A215F-H249R、S024R-N076D-V104I、N018R-N076D-S101G-A232V、N018R-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-A215F-H249R、N018R-S024R-L031F-N076D-N116A-N183D-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N116A-N183D-I198L-T213A-H249R-N269S、N018R-G020R-S024R-N076D-S101A-N116A-I198L-A215F-H249R、N018R-N043R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-G020R-S024R-N076D-S101A-N114T-I198L-G211Q-A215F-H249R、S024R-N043R-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、S024R-N076D-S103A-V104I-A232V、N018R-G020R-T022W-S024R-N076D-S101A-I198L-G211Q-A215F-H249R、S101G-V104I-A232V、N018R-T022W-S024R-N076D-N183D-I198L-T213A-A215F-H249R、N018R-T022W-S024R-N076D-N183D-I198L-G211Q-H249R、N018R-G020R-S024R-N076D-N183D-T213A-H249R、N018R-S024R-N076D-S101A-N183D-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N116A-G211Q-T213A-H249R、N018R-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-G211Q-A215F-H249R-T260A、N076D-H249R、N018R-T022W-S024R-N076D-N183D-G211Q-A215F-H249R、N018R-G020R-S024R-N076D-N116A-G211Q-A215F-H249R、N018R-G020R-S024R-N076D-T213A-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-I198L-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N183D-H249R、N076D-V104I-H249R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-G211Q-T213A-A215F-A232V-Q245R、S024R-N043R-R045T-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-N183D-I198L-A215F-H249R、N018R-N076D-S101G-S103A、G020R-S024R-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-G211Q-H249R、S101G-S103A-A232V、S024R-N076D-S101G-A232V、N018R-T022W-S024R-N076D-S101A-N183D-I198L-G211Q-H249R、N018R-G020R-S024R-N076D-S101A-N183D-I198L-G211Q-A215F-H249R、N018R-G020R-S024R-N076D-N183D-I198L-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-H249R、N018R-G020R-S024R-N076D-N116A-A156V-N183D-G211Q-A215F-H249R-N269S、R045T-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-G020R-S024R-N076D-S101A-N183D-I198L-H249R、N018R-G020R-T022W-S024R-N076D-I198L-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-I198L-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N116A-H249R、N018R-N076D-S101G、N018R-S024R-N076D-N116A-N183D-I198L-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-I198L-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-H249R、N018R-N076D-A232V、N018R-G020R-S024R-N076D-S101A-A232V-Q245R、N018R-N043D-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-N183D-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N116A-G211Q-T213A-N237D-H249R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-G211Q-H249R-R275S、N018R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-T213A-A215F-H249R、S024R-N076D、N018R-S024R-N076D-N183D-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-N116A-N183D-I198L-T213A-A215F-H249R、N076D-V104I-A232V-H249R、N018R-N076D-S103A-A232V、N018R-G020R-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-T213A-H249R、N018R-G020R-S024R-N076D-S101A-N183D-T213A-H249R、N018R-G020R-S024R-N076D-S101A-D175E-N183D-G211Q-A215F-H249R、N018R-G020R-N043D-S078R-S101G-S103A-V104I-L217E-A232V-Q245R-A273E、G020R-S024R-N043D-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、P005S-S101G-S103A-V104I-A232V-Q245R-H249R、S103A-V104I-A232V、N018R-G020R-S024R-V068A-N076D-S101A-N116A-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-I198L-A215F-H249R-R275S、N018R-S024R-N076D-N183D-I198L-G211Q-T213A-H249R、及びN043D-R045T-S101G-S103A-V104I-A232V-Q245Rから選択されるアミノ酸置換の組み合わせを含むアミノ酸配列からなり、このサブチリシン変異体のアミノ酸位置は、配列番号1で示されるB.アミロリケファシエンスのサブチリシンBPN’のアミノ酸配列と対応させて番号付けされる、核酸を提供する。
a)試験方法2による性能指数が、少なくとも1.1、少なくとも1.2、少なくとも1.3、少なくとも1.4、少なくとも1.5、少なくとも1.6、少なくとも1.7、少なくとも1.8、少なくとも1.9、少なくとも2、1.1~約10、1.1~約8、又は更には1.1~約5である;b)試験方法3による性能指数が、少なくとも1.1、少なくとも1.2、少なくとも1.3、少なくとも1.4、少なくとも1.5、少なくとも1.6、少なくとも1.7、少なくとも1.8、少なくとも1.9、少なくとも2、1.1~約10、1.1~約8、又は更には1.1~約5である;c)試験方法4による性能指数が、少なくとも1.0、少なくとも1.1、少なくとも1.2、少なくとも1.3、少なくとも1.4、少なくとも1.5、少なくとも1.6、少なくとも1.7、少なくとも1.8、少なくとも1.9、少なくとも2、1.0~約10、1.0~約8、又は更には1.0~約5である;及び/又はd)試験方法6による性能指数が、少なくとも1.0、少なくとも1.1、少なくとも1.2、少なくとも1.3、少なくとも1.4、少なくとも1.5、少なくとも1.6、少なくとも1.7、少なくとも1.8、少なくとも1.9、少なくとも2、1.0~約10、1.0~約8、又は更には1.0~約5である、のうちの1つの以上を有する。試験方法2、試験方法3、試験方法4、及び試験方法6は、以下の実施例1の表題「試験方法」の節で明記される。本明細書で引用されるすべての変異は、図1に示されるようなBPN’番号付けスキームを利用する。一部の実施形態では、本明細書で参照される変異体は、BPN’番号付与スキームを用い配列番号2のアミノ酸配列と比較されるアミノ酸配列を有する変異体を指す。
49R、S101G-S103A-V104I-P129E-G159E-A232V-N238R-Q245R-N248D、S101G-S103A-V104I-A158E-G159E-S188D-A232V-N238R-Q245R-N248D、S024R-S101G-S103A-V104I-A232V-Q245R-N248D-H249R、T022A-S024R-S101G-S103A-V104I-P129E-L148I-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-A158E-A232V-N238R-Q245R-N248D、S101G-S103A-V104I-S128N-P129E-A232V-N238R-Q245R-N248D、T022A-S101G-S103A-V104I-S128N-G159E-A232V-Q245R-N248D、T022A-S101G-S103A-V104I-S128N-P129E-A158E-A232V-N238R-Q245R-N248D、S101G-S103A-V104I-S128N-P129E-S188D-A232V-Q245R-N248D-H249R、T022A-S024R-S101G-S103A-V104I-S128N-P129E-A158E-S188D-A232V-Q245R-N248D-H249R、S024R-S101G-S103A-V104I-S128N-A158E-G159E-S188D-A232V-Q245R-N248D、T022A-S024K-S101G-S103A-V104I-S128N-A158E-G159E-A232V-Q245R-N248D、S101G-S103A-V104I-P129E-L148I-S188D-A232V-Q245R-N248D、S024R-S101G-S103A-V104I-L148I-A232V-Q245R-N248D、T022A-S101G-S103A-V104I-L148I-S188D-A232V-Q245R-N248D、S024R-S101G-S103A-V104I-S128N-P129E-S188D-A232V-Q245R-N248D、S101G-S103A-V104I-S128N-P129E-A158E-A232V-N238R-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-P129E-L148I-A158E-S188D-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-L148I-A158E-S188D-A232V-Q245R-N248D、S101G-S103A-V104I-L148I-G159E-A232V-Q245R-N248D、T022A-S024R-S101G-S103A-V104I-A158E-S188D-A232V-Q245R-N248D、及びS101G-S103A-V104I-S128N-P129E-A158E-A232V-Q245R-N248D-H249Rから選択されるアミノ酸置換の組み合わせを含むアミノ酸配列からなり、このサブチリシン変異体のアミノ酸位置は、配列番号1で示されるB.アミロリケファシエンスのサブチリシンBPN’のアミノ酸配列と対応させて番号付けされる、サブチリシン変異体を提供する。
45R、G020R-S101G-I198L-A215F-A232V-Q245R、N018R-S024R-N076D-T213A-A215F-H249R、G020R-S078R-S101G-S103A-V104I-N116A-G211Q-A232V-Q245R、G020R-T022W-S078R-S101A-S103A-V104I-N116A-N183D-A215F-A232V-Q245R、G020R-T022W-S078R-S101A-S103A-V104I-N116A-N183D-T213A-A232V-Q245R、S024R-A232V-Q245R、N018R-S024R-N043D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-S024R-N076D-S101A-A215F-H249R、N018R-T022W-S024R-N076D-N116A-T213A-H249R、S101G-S103A-V104I-A232V-Q245R、N018R-S024R-N076D-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-N116A-T213A-A215F-H249R、N043D-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N043D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、G020R-T022W-S078R-S101G-S103A-V104I-N116A-N183D-G211Q-A232V-Q245R、N018R-S024R-N076D-S101A-I198L-G211Q-A215V-H249R、N018R-T022W-S024R-N076D-N116A-G211Q-H249R、G020R-S103A-V104I-A232V-Q245R、G020R-T22W-S101A-S103A-V104I-G211Q-A215F-A232V-Q245R、S024R-N076D-S101G-S103A-V104I-A232V-Q245R、G020R-S101G-S103A-V104I-N116A-A232V-Q245R、N018R-T22W-S024R-N076D-I198L-A215F-H249R、G020R-T022W-S103A-V104I-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-G211Q-T213A-A232V-Q245R、G020R-T022W-S101G-S103A-V104I-G211Q-T213A-A215F-A232V-Q245R、N018R-N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-S101A-I198L-T213A-A215F-H249R、N018R-T22W-S024R-N076D-S101A-A215F-H249R、G020R-R045T-S101G-S103A-V104I-A232V-Q245R、G020R-S078R-S101G-S103A-V104I-T180A-A232V-Q245R、G020R-T022W-S078R-S101G-S103A-V104I-N116A-N183D-A215F-A232V-Q245R、N018R-S101G-S103A-V104I、G020R-T22W-S101A-S103A-V104I-N116A-G211Q-T213A-A215F-A232V-Q245R、N018R-S024R-N076D-S103A-A232V-Q245R、G020R-S078R-S101A-S103A-V104I-N116A-N183D-A232V-Q245R、N018R-S024R-N076D-G211Q-H249R、G020R-S101A-S103A-V104I-T213A-A215F-A232V-Q245R、N018R-G020R-N043D-S101G-S103A-V104I-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-G211Q-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-N116A-G211Q-A215F-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-N116A-G211Q-A232V-Q245R、N018R-S024R-N076D-A232V-H249R、N018R-S024R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-N076D-Q245R、S024R-V104I-Q245R、S101G-A232V、G020R-T22W-S101A-S103A-V104I-N116A-G211Q-A215F-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-I198L-T213A-H249R、G020R-T022W-S078R-S101A-S103A-V104I-A232V-Q245R、G020R-T022W-S078R-S101A-S103A-V104I-I198L-A232V-Q245R、S024R-Q245R-H249R、G020R-S101G-S103A-V104I-N116A-G211Q-A232V-Q245R、N018R-T22W-S024R-N076D-N116A-G211Q-H249R、S024R-S101G-V104I-H249R、N018R-S024R-N076D-N116A-I198L-G211Q-T213A-A215F-H249R、N018R-S024R-V104I、G020R-T022W-S078R-S101A-S103A-V104I-N183D-I198L-T213A-A215F-A232V-Q245R、N018R-G020R-T22W-S024R-N076D-N116A-N183D-I198L-T213A-H249R、G020R-T022W-S101A-S103A-V104I-A232V-Q245R、Q012H-G020R-S078R-S101G-S103A-V104I-I198L-G211Q-T213A-A232V-Q245R、N018R-S024R-N076D-S101A-G211Q-A215F-H249R、N018R-S024R-N076D-T213A-H249R、S024R-V104I-H249R、N018R-T022W-S024R-N076D-G211Q-H249R、N018R-N076D-S103A-V104I-H249R、N043R-N076D-S101G-S103A-V104I-L217E-A232V-Q245R、G020R-S078R-S101G-S103A-V104I-N183D-G211Q-T213A-A232V-Q245R-E271G、N018R-T022W-S024R-N076D-S101A-N116A-I198L-A215F-H249R、N018R-S024R-N043D-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-S024R-N076D-S101A-I198L-A215F-H249R、N018R-T022W-S024R-N076D-N116A-I198L-G211Q-T213A-H249R、N018R-S024R-N076D-S101A-N116A-T213A-A215F-H249R、G020R-N043D-R045T-S078R-S101G-S103A-V104I-A232V-Q245R、R045T-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-T22W-S024R-N076D-S101A-N116A-A215F-H249R、N043D-S101G-S103A-V104I-A232V-Q245R-N269R、G020R-T022W-S078R-S101A-S103A-V104I-N116A-N183D-T213A-A215F-A232V-Q245R、N018R-S024R-N076D-N116A-G211Q-T213A-A215F-H249R、S024R-S103A-M175L-A232V-H249R、N018R-S024R-N076D-N116A-T213A-H249R、G020R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、G020R-S078R-S101A-S103A-V104I-N116A-N183D-G211Q-T213A-A215F-A232V-Q245R、S024R-N043R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-S024R-N076D-S101A-N116A-I198L-T213A-A215F-H249R、N043R-R045T-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-S101A-I198L-G211Q-Q245R、G020R-S024R-N043D-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、S024R-A232V、G020R-S078R-S101A-S103A-V104I-N116A-N183D-G211Q-A232V-Q245R、S024R-N076D-S101G-A232V-Q245R、N018R-N076D-S101G-S103A-V104I-H249R、N018R-S024R-N076D-I198M-G211Q-T213A-A215F-H249R、N018R-T22W-S024R-N076D-S101A-I198L-A215F-H249R、N018R-N043R-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、G020R-T022W-S103A-G211Q-T213A-A215F-A232V-Q245R、G020R-S078R-S101A-S103A-V104I-N116A-N183D-G211Q-T213A-A232V-Q245R、R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-T22W-S024R-N076D-S101A-G211Q-T213A-H249R、N018R-S024R-N076D-N116A-I198L-A215F-H249R-V268G、N018R-T022W-S024R-N076D-S101A-G211Q-H249R、N018R-T022W-S024R-N076D-S101A-N116A-I198L-G211Q-H249R、S101G-S103A-V104I-Q245R、N018R-N076D-S101G-A232V-Q245R、N018R-G020R-R045T-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-S101A-N116A-I198L-H249R、N018R-T022W-S024R-N076D-N116A-I198L-T213A-H249R、S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、G020R-N043R-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-N043D-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、R045T-S101G-S103A-V104I-A232V-Q245R-N269R、S024R-S103A-A232V、N018R-S024R-N076D-S10
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-H249R、N018R-T022W-S024R-N076D-S101A-N116A-G211Q-T213A-H249R、N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-N076D-S101G-V104I-H249R、N018R-T022W-S024R-N076D-S101A-T213A-A215F-H249R、N018R-T22W-S024R-N076D-S101A-N116A-I198L-A215F-H249R、N018R-G020R-S101G-S103A-V104I-A232V-Q245R-H249R、S101G-S103A-V104I-A232V-Q245R-H249R-N269R、S024R-N076D-Q245R、N018R-G020R-N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-S024R-N076D-A215F-H249R、N018R-S024R-N076D-S101A-N116A-N183D-I198L-T213A-H249R、N018R-G020R-S024R-N076D-G211Q-A215F-H249R、N043D-S101G-S103A-V104I-A232V-Q245R、G020R-T22W-S078R-S101A-S103A-V104I-N116A-N183D-A215F-A232V-Q245R、N018R-S024R-N076D-I198L-G211Q-A215F-H249R、N043R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N043R-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、G020R-N043D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-T022W-S024R-N076D-S101A-T213A-H249R、G020R-T022W-S101A-N116A-I198L-G211Q-T213A-A215F-H249R、N043R-R045T-S078R-S101G-S103A-V104I-N218S-A232V-Q245R、N018R-S103A、G020R-T22W-S101G-S103A-V104I-N116A-N183D-A215F-A232V-Q245R、N018R-S024R-N076D-S101A-H249R、N018R-T022W-S024R-N076D-G211Q-T213A-H249R、S024R-N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-A232V-Q245R、G020R-S101A-S103A-V104I-N116A-N183D-G211Q-T213A-A215F-A232V-Q245R、K027R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、G020R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-G020R-S024R-N076D-N116A-N183D-T213A-A215F-H249R、N018R-S024R-N076D-V104I、S101G-S103A-V104I-A232V-H249R、N018R-S024R-N076D-N116A-N183D-G211Q-H249R、N018R-G020R-S024R-N076D-N116A-A215F-H249R、N018R-S024R-N076D-N183D-T213A-A215F-H249R、N018R-T022W-S024R-N076D-I198L-G211Q-H249R、N043D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R-R275S、G020R-T022W-S101A-S103A-V104I-N116A-N183D-G211Q-A232V-Q245R、N018R-T022W-S024R-N076D-S101A-I198L-G211Q-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-I198L-G211Q-T213A-A215F-H249R、N018R-G020R-S024R-N076D-N183D-H249R、N018R-S024R-N076D-N116A-I198L-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N116A-G211Q-H249R、V004M-N018R-S024R-N076D-N116A-I198L-G211Q-T213A-H249R、V104I-A232V-H249R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-G211Q-A215F-A232V-Q245R、G020R-S101A-S103A-V104I-N116A-N183D-G211Q-A232V-Q245R-T274I、G020R-S101A-S103A-V104I-T213A-A232V-Q245R、G020R-S101G-S103A-V104I-N116A-N183D-G211Q-T213A-A232V-Q245R、G020R-S024R-N043D-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-S024R-N076D-S103A-H249R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-G211Q-A215F-H249R、N018R-G020R-S024R-N076D-N116A-N183D-I198L-H249R、N018R-T022W-S024R-N076D-N116A-I198L-A215F-H249R、N018R-S024R-N076D-S101A-G211Q-T213A-A215F-H249R-A270V、N018R-N043D-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、G020R-T022W-S101G-S103A-V104I-N183D-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-T213A-H249R、N018R-T022W-S024R-N076D-I198L-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-I198L-T213A-H249R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-A232V-Q245R、N018R-T22W-S024R-N076D-N116A-I198L-T213A-H249R、N043R-R045T-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-S024R-N076D-S101G-S103A-V104I-A232V、S101G-H249R、S024R-N076D-S101G-S103A-V104I-M175L-H249R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-A232V-Q245R-N269S、N018R-S024R-N076D-S101A-N116A-I198L-H249R、N018R-T022W-S024R-N076D-N116A-H249R、N018R-G020R-S024R-N076D-S101A-N183D-I198L-A215F-H249R、N018R-S024R-N076D-T213A-A215F-H249R-T260K、N018R-S024R-N076D-N116A-G211Q-T213A-H249R、N018R-G020R-T022W-S024R-N076D-N116A-I198L-H249R、S024R-N076D-S101G-S103A-V104I-Q245R、S024R-N076D-S103A-H249R、N018R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-S024R-N076D-I198L-G211Q-H249R、N018R-T022W-S024R-N076D-S101A-I198L-G211Q-T213A-H249R、G020R-S024R-R045T-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-S024R-N076D-N183D-G211Q-T213A-H249R、N018R-N043D-R045T-S078R-S101G-S103A-V104I-A232V-Q245R-A272D、N018R-S024R-N076D-N116A-I198L-T213A-A215F-H249R、N018R-T22W-S024R-N076D-S101A-I198L-H249R、N018R-T022W-S024R-N076D-N116A-I198L-H249R、S024R-N076D-S101G-S103A-A232V、S024R-S103A-V104I、N018R-S024R-N076D-S101A-N116A-N183D-G211Q-A215F-H249R、S024R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、G020R-S101G-S103A-V104I-N116A-N183D-A232V-Q245R、S024R-N043D-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、G020R-T022W-S101A-S103A-V104I-N183D-G211Q-T213A-A215F-A232V-Q245R、G020R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-S024R-N076D-S101A-N116A-I198L-G211Q-A215F-H249R、G020R-S101A-S103A-V104I-N116A-N183D-A215F-A232V-Q245R、N018R-N043R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-S024R-N076D-I198L-T213A-H249R、N018R-S024R-N076D-N116A-N183D-T213A-H249R、G020R-N043D-S101G-S103A-V104I-A232V-Q245R-N269R、S024R-N076D-S103A-Q245R、N018R-T022W-S024R-N076D-S101A-N116A-G211Q-T213A-A215F-H249R、S103A-V104I-Q245R、N018R-T022W-S024R-N076D-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-N116A-N183D-I198L-H249R、N018R-T022W-S024R-N076D-I198L-G211Q-T213A-H249R、N018R-S024R-N076D-N116A-N183D-G211Q-T213A-A215F-H249R、N018R-G020R-N043D-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-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022W-S024R-N076D-N116A-A215F-H249R、N043R-N076D-S101G-S103T-V104I-A232V-Q245R-H249R-N269R、G020R-S078R-S101A-S103A-V104I-G115E-N116A-N183D-G211Q-T213A-A232V-Q245R、N018R-S024R-N076D-I198L-H249R、N018R-S024R-N076D-S101A-N116A-N183D-H249R、G020R-S101G-S103A-V104I-N116A-N183D-G211Q-A232V-Q245R、N018R-S024R-N076D-S101G、N076D-S101G-A232V-Q245R、N018R-N076D-S101G-S103A-V104I-Q245R、N018R-R045T-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-S024R-N076D-A215F-H249R、N018R-V104I-A232V、N043D-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、S024R-N076D-S101G-A232V-H249R、S103A-A232V-Q245R、G020R-S101G-S103A-V104I-N116A-N183D-G211Q-T213A-A215F-A232V-Q245R、N018R-G020R-S024R-N076D-N116A-N183D-I198L-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-S101A-I198L-G211Q-A215F-H249R、S024R-N076D-S103A-V104I-H249R、S024R-S101G-S103A-V104I、G020R-S101G-S103A-V104I-N116A-N183D-G211Q-A215F-A232V-Q245R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-A215F-H249R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-G211Q-T213A-A215F-A232V-Q245R、G020R-S024R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-N116A-N183D-T213A-H249R、N018R-G020R-S024R-N076D-A131T-A215F-H249R、N018R-S024R-N076D-S101A-N116A-N183D-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N116A-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-I198L-A215F-H249R、N018R-T022W-S024R-N076D-N183D-G211Q-H249R、N018R-T022W-S024R-N076D-S101A-N116A-T213A-A215F-H249R、N018R-G020R-S024R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N043R-S101G-S103A-V104I-Q245R-H249R、N018R-N076D-A232V-H249R、N018K-N076D-S078R-S101G-S103A-V104I-L217E-A232V-Q245R-N269R、N018R-G020R-S024R-N043D-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-S101A-N116A-T213A-A215F-H249R-L267I、A232V-H249R、N018R-G020R-S024R-N076D-N116A-G211Q-T213A-A215F-H249R、N076D-V104I-Q245R、N018R-G020R-S024R-N076D-N183D-I198L-G211Q-A215F-H249R、N018R-S024R-N076D-S101A-G211Q-T213A-H249R、S024R-S101G-S103A-A232V、N018R-G020R-T022W-S024R-N076D-N116A-N183D-I198L-T213A-A215F-H249R、N018R-G020R-S024R-N076D-N116A-N183D-I198L-G211Q-T213A-H249R、N018R-G020R-T022W-S024R-N076D-S101A-A215F-H249R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-G211Q-A215F-A232V-Q245R、N018R-S024R-N076D-N116A-I198L-G211Q-H249R、S103A-A232V-H249R、N018R-G020R-S024R-N076D-N116A-N183D-I198L-A215F-H249R、N018R-S024R-N076D-N116A-N183D-I198L-T213A-H249R、N018R-T022W-S024R-N076D-N183D-T213A-H249R、N018R-S024R-N076D-S101A-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-G211Q-H249R、N018R-R045T-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-G020R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-N116A-I198L-T213A-A215F-H249R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-G211Q-T213A-A232V-Q245R、N018R-G020R-S024R-N076D-I198L-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-G211Q-H249R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-A232V-Q245R-T274I、S024R-S103A-Q245R-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-H249R、N018R-S024R-N076D-S101A-I198L-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-N116A-I198L-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-T213A-H249R、N018R-N043D-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-T022W-S024R-N076D-N116A-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N183D-I198L-T213A-H249R、N043D-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-S024R-N076D-I198L-G211Q-T213A-A215F-H249R、N018R-G020R-S024R-N076D-N116A-N183D-T213A-H249R、S103A-A232V、N018R-T022W-S024R-N076D-N116A-N183D-A215F-H249R、N018R-S024R-N076D-S101A-N116A-H249R、N018R-N043R-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-S101A-N183D-G211Q-A215F-H249R、N043R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-I198L-T213A-H249R、N018R-S024R-N076D-N183D-I198L-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N183D-G211Q-H249R、N018R-G020R-S024R-N076D-I198L-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N183D-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-I198L-H249R、N018R-S024R-N076D-N183D-I198L-G211Q-H249R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-T213A-A232V-Q245R、N018R-G020R-S024R-N076D-N116A-N183D-G211Q-T213A-H249R、N018R-S024R-N076D-N116A-N183D-I198L-G211Q-T213A-A215F-H249R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-A215F-A232V-Q245R、N018R-S024R-N076D-S101A-N183D-H249R、N018R-S024R-N076D-A232V、N018R-T022W-S024R-N076D-S101A-N116A-H249R、G020R-S101A-S103A-V104I-N116A-N183D-I198L-G211Q-T213A-A215F-A232V-Q245R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-G211Q-A232V-Q245R-N263S、S024R-N076D-S101G-V104I-A232V-H249R、N043R-S078R-S101G-S103A-V104I-A232V-Q245R、S024R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-S024R-N076D-S101A-N183D-I198L-T213A-A215F-H249R、N018R-G020R-S024R-N076D-I198L-A215F-H249R、N018R-G020R-S024R-N076D-S101A-N116A-T213A-H249R、N018R-S024R-N076D-S101A-V197A-T213A-A215F-H249R、S024R-S101G-S103A、N018R-S024R-N076D-S101A-N116A-G211Q-A215F-H249R、N043R-N076D-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、S024R-V104I-A232V、N018R-S024R-N076D-N183D-G211Q-H249R、G020R-N043R-R045T-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-S101A-N11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24R-N076D-N116A-N183D-I198L-G211Q-H249R、N018R-S024R-N076D-S101G-Q245R、N018R-S024R-N076D-S101A-N116A-N183D-I198L-T213A-A215F-H249R、N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-N116A-I198L-T213A-A215F-H249R、N076D-V104I-A232V-Q245R、K027R-N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-S101A-N183D-T213A-A215F-H249R、N018R-S024R-N076D-S103A-V104I-L135I-A232V、N018R-G020R-T022W-S024R-N076D-N183D-I198L-G211Q-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-A215F-H249R、N018R-S024R-N076D-S101A-N116A-N183D-G211Q-H249R、N018R-T022W-S024R-N076D-N183D-G211Q-T213A-A215F-H249R、N076D-S101G-S103A-V104I-A232V-H249R、P005S-N018R-T022W-S024R-N076D-S101A-T213A-A215F-H249R、N018R-S024R-N076D-N116A-N183D-A215F-H249R、N018R-S024R-N076D-N183D-I198L-A215F-H249R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-H249R、N018R-T022W-S024R-N076D-N116A-N183D-G211Q-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N183D-G211Q-T213A-H249R、N018R-G020R-S024R-N076D-N116A-I198L-H249R、N018R-S024R-N076D-N183D-G211Q-T213A-H249R、N018R-S024R-N076D-S101A-N116A-N183D-T213A-H249R、N018R-S024R-N076D-N116A-N183D-I198L-A215F-H249R、N018R-T022W-S024R-N076D-N183D-I198L-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-N183D-H249R、N018R-T022W-S024R-N076D-S101A-N183D-I198L-A215F-H249R、N018R-G020R-N043D-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、G020R-T022W-S101A-S103A-V104I-N183D-I198L-A215F-A232V-Q245R、N076D-S101G-S103A-V104I-H249R、N018R-G020R-S024R-N076D-N183D-I198L-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N183D-A215F-H249R、N018R-G020R-S024R-N076D-G211Q-T213A-H249R、N018R-S024R-N076D-N116A-N183D-G211Q-T213A-H249R、N018R-S024R-N076D-N116A-N183D-I198L-H249R、N018R-G020R-S024R-N076D-G211Q-N243D-H249R、N018R-G020R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-T022W-S024R-N076D-N183D-I198L-G211Q-T213A-H249R、N018R-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-T213A-H249R、N018R-T022W-S024R-N076D-N116A-I198L-G211Q-T213A-A215F-H249R、S024R-N076D-S101G、N018R-G020R-S024R-N076D-S101A-I198L-T213A-A215F-H249R、N018R-T022W-S024R-N076D-N116A-N183D-G211Q-T213A-H249R、N018R-G020R-S024R-N076D-N183D-A215F-H249R、N018R-N043D-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-T022W-S024R-N076D-N116A-N183D-G211Q-T213A-Q245R、G020R-S024R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-G020R-R045T-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-S024R-N076D-S101A-N183D-I198L-G211Q-H249R、N018R-T022W-S024R-N076D-N183D-G211Q-T213A-H249R、N018R-G020R-S024R-N076D-N116A-I198L-G211Q-A215F-H249R-N269S、N018R-G020R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-A215F-H249R、G020R-T022W-S101A-S103A-V104I-N183D-T213A-A215F-A232V-Q245R、N018R-S024R-N076D-A086V-S101A-N183D-I198L-G211Q-H249R、N018R-N076D-S101G-I198T-A232V、N018R-G020R-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N183D-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-N183D-H249R-A248T、N018R-N076D-V104I-Q245R-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-A215F-H249R、N018R-T022W-S024R-N076D-N116A-N183D-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-G211Q-T213A-A215F-H249R、N018R-G020R-S024R-N076D-S101A-H249R、N018R-G020R-S024R-N076D-S101A-N116A-T213A-A215F-H249R、N018R-T022W-S024R-N076D-N116A-N183D-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-N116A-N183D-I198L-G211Q-T213A-H249R、N043R-R045T-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、N043R-R045T-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-N076D-S101G-V104I、G020R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-H249R、N043D-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-H249R、N018R-N076D-V104I、N018R-G020R-N043D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-G020R-T022W-S024R-N076D-N183D-G211Q-H249R、N018R-S024R-N076D-S101A-N183D-I198L-G211Q-A215F-H249R、S101G-V104I、N018R-T022W-S024R-N076D-N116A-N183D-I198L-G211Q-T213A-A215F-H249R、N018R-G020R-S024R-N076D-S101A-N183D-G211Q-T213A-A215F-H249R、N018R-G020R-S024R-N076D-N116A-N183D-A215F-H249R-N263D、N018R-T022W-S024R-N076D-S101A-N183D-H249R、N018R-S024R-N076D-S101A-N116A-N183D-I198L-A215F-H249R、N018R-T022W-S024R-N076D-N116A-I198L-A215F-H249R-R269H、N018R-N043D-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R、N018R-S024R-R045T-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、S078R-S101G-S103A-V104I-L217E-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-S101A-N183D-I198L-T213A-A215F-H249R、N018R-G020R-S024R-N076D-N183D-I198L-T213A-H249R、N018R-G020R-T022W-S024R-N076D-N116A-I198L-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-G211Q-H249R、N018R-G020R-T022W-S024R-N076D-S101A-I198L-G211Q-T213A-H249R、N018R-G020R-T022W-S024R-N076D-H249R、G020R-T022W-S101G-S103A-V104I-N116A-N183D-I198L-G211Q-T213A-A215F-A232V-Q245R、V104I-A232V、N018R-G020R-T022W-S024R-N076D-S101A-N116A-N183D-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N183D-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-N183D-I198L-G211Q-T213A-H249R、N018R-T022W-S024R
-N076D-S101A-N183D-I198L-H249R、N043D-R045T-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-G020R-S024R-N076D-S101A-N183D-I198L-G211Q-H249R、N018R-G020R-N043R-S101G-S103A-V104I-L217E-A232V-Q245R、S024R-N043R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N043R-R045T-N076D-S078R-S101G-S103A-V104I-Y166F-A176P-A179V-N184T-A187P-A194P、N018R-T022W-S024R-D041E-N076D-S101A-S160T-N183D-G211Q-T213A-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-I198L-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-I198L-T213A-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-T213A-H249R、N018R-G020R-S024R-N076D-I198L-T213A-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-I198L-G211Q-H249R、N018R-G020R-S024R-N076D-N183D-G211Q-A215F-H249R、S024R-N076D-V104I、N018R-N076D-S101G-A232V、N018R-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-A215F-H249R、N018R-S024R-L031F-N076D-N116A-N183D-G211Q-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N116A-N183D-I198L-T213A-H249R-N269S、N018R-G020R-S024R-N076D-S101A-N116A-I198L-A215F-H249R、N018R-N043R-N076D-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-G020R-S024R-N076D-S101A-N114T-I198L-G211Q-A215F-H249R、S024R-N043R-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、S024R-N076D-S103A-V104I-A232V、N018R-G020R-T022W-S024R-N076D-S101A-I198L-G211Q-A215F-H249R、S101G-V104I-A232V、N018R-T022W-S024R-N076D-N183D-I198L-T213A-A215F-H249R、N018R-T022W-S024R-N076D-N183D-I198L-G211Q-H249R、N018R-G020R-S024R-N076D-N183D-T213A-H249R、N018R-S024R-N076D-S101A-N183D-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N116A-G211Q-T213A-H249R、N018R-S078R-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-G211Q-A215F-H249R-T260A、N076D-H249R、N018R-T022W-S024R-N076D-N183D-G211Q-A215F-H249R、N018R-G020R-S024R-N076D-N116A-G211Q-A215F-H249R、N018R-G020R-S024R-N076D-T213A-H249R、N018R-G020R-T022W-S024R-N076D-N116A-N183D-I198L-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N183D-H249R、N076D-V104I-H249R、G020R-T022W-S101A-S103A-V104I-N116A-N183D-G211Q-T213A-A215F-A232V-Q245R、S024R-N043R-R045T-S078R-S101G-S103A-V104I-L217E-A232V-Q245R、N018R-G020R-T022W-S024R-N076D-N183D-I198L-A215F-H249R、N018R-N076D-S101G-S103A、G020R-S024R-S101G-S103A-V104I-A232V-Q245R-N269R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-G211Q-H249R、S101G-S103A-A232V、S024R-N076D-S101G-A232V、N018R-T022W-S024R-N076D-S101A-N183D-I198L-G211Q-H249R、N018R-G020R-S024R-N076D-S101A-N183D-I198L-G211Q-A215F-H249R、N018R-G020R-S024R-N076D-N183D-I198L-H249R、N018R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-H249R、N018R-G020R-S024R-N076D-N116A-A156V-N183D-G211Q-A215F-H249R-N269S、R045T-N076D-S101G-S103A-V104I-A232V-Q245R-H249R、N018R-G020R-S024R-N076D-S101A-N183D-I198L-H249R、N018R-G020R-T022W-S024R-N076D-I198L-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-I198L-G211Q-A215F-H249R、N018R-G020R-T022W-S024R-N076D-N116A-H249R、N018R-N076D-S101G、N018R-S024R-N076D-N116A-N183D-I198L-T213A-A215F-H249R、N018R-G020R-T022W-S024R-N076D-S101A-N116A-I198L-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-H249R、N018R-N076D-A232V、N018R-G020R-S024R-N076D-S101A-A232V-Q245R、N018R-N043D-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、N018R-T022W-S024R-N076D-N183D-T213A-A215F-H249R、N018R-S024R-N076D-S101A-N116A-G211Q-T213A-N237D-H249R、N018R-G020R-S024R-N076D-S101A-N116A-N183D-G211Q-H249R-R275S、N018R-T022W-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-T213A-A215F-H249R、S024R-N076D、N018R-S024R-N076D-N183D-G211Q-A215F-H249R、N018R-T022W-S024R-N076D-N116A-N183D-I198L-T213A-A215F-H249R、N076D-V104I-A232V-H249R、N018R-N076D-S103A-A232V、N018R-G020R-S024R-N076D-S101A-N116A-N183D-I198L-G211Q-T213A-H249R、N018R-G020R-S024R-N076D-S101A-N183D-T213A-H249R、N018R-G020R-S024R-N076D-S101A-D175E-N183D-G211Q-A215F-H249R、N018R-G020R-N043D-S078R-S101G-S103A-V104I-L217E-A232V-Q245R-A273E、G020R-S024R-N043D-R045T-N076D-S101G-S103A-V104I-A232V-Q245R、P005S-S101G-S103A-V104I-A232V-Q245R-H249R、S103A-V104I-A232V、N018R-G020R-S024R-V068A-N076D-S101A-N116A-T213A-A215F-H249R、N018R-T022W-S024R-N076D-S101A-I198L-A215F-H249R-R275S、N018R-S024R-N076D-N183D-I198L-G211Q-T213A-H249R、及びN043D-R045T-S101G-S103A-V104I-A232V-Q245Rから選択されるアミノ酸置換の組み合わせを含むアミノ酸配列からなり、このサブチリシン変異体のアミノ酸位置は、配列番号1で示されるB.アミロリケファシエンスのサブチリシンBPN’のアミノ酸配列と対応させて番号付けされる、サブチリシン変異体を提供する。
本発明の変異体プロテアーゼをコードする本発明の改変ポリヌクレオチドを生成するのに好適な様々な方法が当該技術分野において既知であり、限定するものではないが、例えば、部分飽和変異導入、系統的変異導入、挿入変異導入、欠失変異導入、ランダム変異導入、部位特異的変異導入、及び定向進化、並びに様々な他の組み換え手法が挙げられる。改変されたポリヌクレオチド及びタンパク質(例えば、変異体プロテアーゼ)の製造方法としては、遺伝子の非相同組み換えに基づく方法、例えばITCHY(Ostermeier et al.,7:2139~44[1999]を参照されたい)、SCRACHY(Lutz et al.98:11248~53[2001]を参照されたい)、SHIPREC(Sieber et al.,19:456~60[2001]を参照されたい)、及びNRR(Bittker et al.,20:1024~9[2001];Bittker et al.,101:7011~6[2004])を参照されたい、並びにランダムな及び標的とされる変異、欠失及び/又は挿入を組み込むためにオリゴヌクレオチドを使用することに基づく方法(Ness et al.,20:1251~5[2002];Coco et al.,20:1246~50[2002];Zha et al.,4:34~9[2003];Glaser et al.,149:3903~13[1992]を参照されたい)などのDNAシャフリング方法が挙げられる。
本発明は、本明細書に記載の本発明の少なくとも1種のポリヌクレオチドを含む単離された又は組み換えベクター(例えば、本明細書に記載の本発明の変異体プロテアーゼをコードするポリヌクレオチド)、本発明の少なくとも1種の核酸又はポリヌクレオチドを含む単離された又は組み換えプロテアーゼ発現ベクター又は発現カセット、本発明の少なくとも1種の核酸又はポリヌクレオチドを含む単離された、実質的に純粋の、又は組み換えDNAコンストラクト、本発明の少なくとも1種のポリヌクレオチドを含む単離された又は組み換え細胞、本発明の少なくとも1種のポリヌクレオチドを含む細胞を含む細胞培養物、本発明の少なくとも1種の核酸又はポリヌクレオチドを含む細胞培養物、並びにこのようなベクター、核酸、発現ベクター、発現カセット、DNAコンストラクト、細胞、細胞培養物、又はこれらの任意の組み合わせ又はこれらの混合物などを1種以上含む組成物を提供する。
一部の実施形態では、本発明のプロテアーゼ変異体は、補助成分及びプロテアーゼ変異体を含む組成物で使用することができ、ここで、組成物は布地ケア製品及びホームケア製品である。
特に記載がない限り、本明細書に提供される成分又は組成物の濃度はすべて、成分又は組成物の活性レベルに対するものであり、市販の供給源に存在し得る不純物、例えば、残留溶媒又は副生成物は除外される。酵素成分の重量は活性タンパク質の合計に基づくものである。百分率及び比率はすべて、特に指示しない限り、重量で計算される。百分率及び比率はすべて、特に指示しない限り、組成物全体を基準にして計算される。例示された洗剤組成物において、酵素濃度は、組成物の合計重量に基づき純粋な酵素濃度として表現され、かつ特に記載のない限り、洗剤成分は組成物の合計重量に基づき表現される。
本発明のクリーニング組成物は、任意の好適な形態へと配合され、及び配合者により選択された任意の好適な方法により調製される(例えば、米国特許第同第5,879,584号、同第5,691,297号、同第5,574,005号、同第5,569,645号、同第5,565,422号、同第5,516,448号、同第5,489,392号、同第5,486,303号、同第4,515,705号、同第4,537,706号、同第4,515,707号、同第4,550,862号、同第4,561,998号、同第4,597,898号、同第4,968,451号、同第5,565,145号、同第5,929,022号、同第6,294,514号及び同第6,376,445号を参照されたい)。
一部の実施形態では、本発明のクリーニング組成物は表面(例えば、食器類)、洗濯物、硬質表面及びコンタクトレンズのクリーニングにおける使用が見出される。一部の実施形態では、表面の少なくとも一部を、未希釈形態の、又は水性溶液で希釈した形態の少なくとも1種の本発明のクリーニング組成物の一実施形態と接触させ、次いで表面を任意選択で洗浄及び/又はすすぎ洗いする。本発明の目的に関し、「洗浄」には擦ること及び機械的洗浄が含まれるが、これらに限定されない。一部の実施形態では、本発明のクリーニング組成物は、溶液中約500ppm~約15,000ppmの濃度で使用される。洗浄溶媒が水である一部の実施形態では、水温は、典型的には約5℃~約90℃の範囲である。
本発明は、以降の実施例により、更に詳細に記載されるが、この記載により本発明の範囲が請求されたものとして、本発明の範囲を制限することを意図するものではない。
ASF Co.,Florham Park,NJ)、Huntsman(Huntsman Petrochemical Corp.,Salt Lake City,UT)、Shell Chemicals(Shell Chemicals,Inc.,London,UK)、Stepan(Stepan,Northfield,IL)、Clariant(Clariant,Sulzbach,Germany)、Industrial Zeolite(Industrial Zeolite Ltd.,Grays,Essex,UK)、Jungbunzlauer(Jungbunzlauer,Basel,Switzerland)、Solvay(Solvay,Brussels,Belgium)、3V Sigma(3V Sigma,Bergamo,Italy)、Innospec(Innospec,Ellesmere Port,UK)、Thermphos(Thermphos,Vlissiggen-Ost,the Netherlands)、Ciba Specialty(Ciba Specialty Chemicals,Basel,Switzerland)、Dow Corning(Dow Corning,Barry,UK)、Enichem(Enichem Iberica,Barcelona,Spain)、Fluka Chemie AG(Fluka Chemie AG,Buchs,Switzerland)、Gist-Brocades(Gist-Brocades,NV,Delft,the Netherlands)、Dow Corning(Dow Corning Corp.,Midland,MI)、Mettler-Toledo(Mettler-Toledo Inc,Columbus,OH)、RB(Reckitt-Benckiser,Slough,UK)、及びMicrosoft(Microsoft,Inc.,Redmond,WA)。
界面活性剤材料は、次の企業から得ることができる:BASF(Ludwigshafen,Germany)(Lutensol(登録商標));Shell Chemicals(London,UK);Stepan(Northfield,Illinois,USA);Huntsman(Huntsman,Salt Lake City,Utah,USA);Clariant(Sulzbach,Germany(Praepagen(登録商標)))。
アッセイ及び試験方法
本実施例は、本発明の展開に使用される様々な試験方法及びアッセイを記載する。提供されるプロトコール由来の任意の変法が関連する実施例に示される。
試験方法1
染料又は顔料材料が本発明の意図する布地色調剤であるか否かを定義するためのプロトコールを以下に記載する。
試験方法2では、顆粒型洗剤組成物10(上記表Dを参照されたい)を用い、以下に記載のBMIマイクロスウォッチアッセイを実施した。洗濯洗剤を硬度12gpg(205.2ppm)の水に溶解させ、水温を16℃に調整し、対象とするプロテアーゼ変異体酵素を添加した。次いで、記載されるBMIマイクロスウォッチアッセイ毎に酵素変異体の性能を測定する。性能指数は、プロテアーゼ変異体酵素の性能を、配列番号2のアミノ酸配列を有するB.レンタスのGG36サブチリシン酵素と比較することで決定する。すべての条件で、酵素の使用濃度は0.1~5ppm範囲である。プロテアーゼ変異体酵素のうち、性能指数1.1以上のものが冷水用プロテアーゼとして示される。
試験方法3では、顆粒型洗剤組成物7(上記表Dを参照されたい)を用い、以下に記載のBMIマイクロスウォッチアッセイを実施する。洗濯洗剤を硬度6gpg(102.6)の水に溶解させ、水温を16℃に調整し、対象とする、プロテアーゼGG36変異体酵素を添加する。次いで、記載されるBMIマイクロスウォッチアッセイ毎にプロテアーゼGG36変異体酵素の性能を測定する。性能指数は、プロテアーゼGG36変異体酵素の性能を、配列番号2のアミノ酸配列を有するB.レンタスのGG36サブチリシン酵素と比較することで決定する。すべての条件で、酵素の使用濃度は0.1~5ppm範囲である。プロテアーゼGG36の変異体のうち、性能指数1.1以上のものが冷水用プロテアーゼとして示される。
試験方法4では、顆粒型洗剤組成物7(上記表Dを参照されたい)を用い、BMIマイクロスウォッチアッセイを実施する。洗濯洗剤を硬度6gpg(102.6ppm)の水に溶解させ、水温を16℃に調整し、対象とするGG36プロテアーゼ変異体酵素を添加する。次いで、記載されるBMIマイクロスウォッチアッセイ毎に酵素変異体の性能を測定する。性能指数は、GG36プロテアーゼの変異体酵素の性能を参照酵素GG36-A158Eの性能と比較することによって決定される。GG36-A158E参照酵素は配列番号2のB.レンタスのサブチリシンGG36プロテアーゼのアミノ酸配列の位置158でアラニンがグルタミン酸へと単独置換されている(すなわち、A158E変異)。すべての場合で、酵素は0.1~5ppmの範囲で投与する。性能指数1.0以上のプロテアーゼGG36変異体が、冷水用プロテアーゼとして示される。
試験方法6では、表1-2の洗剤36a~36nのうちのいずれか1種を用いてBMIマイクロスウォッチアッセイを実施する。表1-2に記載の水硬度を有する水に洗剤を溶解させ、水温を16℃に調整する。次いで、記載されるBMIマイクロスウォッチアッセイ毎に酵素変異体の性能を決定する。性能指数は、変異体の性能を配列番号2の酵素と比較することで決定される。すべての場合で酵素投与量は0.1~5ppmである。酵素のうち、性能指数1.1以上のものが冷水用プロテアーゼとして示される。
96ウェルマイクロタイタープレートでタンパク質含量を測定するためのTCAアッセイ。
セリンプロテアーゼ変異体のプロテアーゼ活性を測定するために、N-スクシニル-L-アラニル-L-アラニル-L-プロリル-L-フェニル-p-ニトロアニリド(suc-AAPF-pNA)の加水分解を計測した。使用した試薬溶液は、以下のものであった:0.005%のTWEEN(登録商標)-80を含有している100mMトリス/HCl(pH 8.6)(トリス希釈緩衝液)、1mM CaCl2及び0.005%のTWEEN(登録商標)-80を含有している100mMトリス緩衝液(pH 8.6)(トリス/Ca緩衝液)、並びに160mM suc-AAPF-pNA/DMSO(suc-AAPF-pNA保存溶液)(Sigma:S-7388)。suc-AAPF-pNA希釈標準溶液を調製するために、1mLのsuc-AAPF-pNA原液を100mLのトリス/Ca緩衝液に加え、少なくとも10秒にわたってウェルをよく混合した。10μLの希釈プロテアーゼ溶液を96ウェルMTPの各ウェルに加え、直ちに1mg/mLのsuc-AAPF-pNA希釈標準溶液190μLを加えてアッセイを実施した。溶液を5秒にわたって混合し、吸光度の変化を、25℃にて、405nmで、MTPリーダーの動的解析モードにより読み取りした(5分毎に25回読み取り)。プロテアーゼ活性はAUとして表記される(活性=ΔOD・min-1mL-1)。
本明細書に記載のセリンプロテアーゼ濃度及び比活性を、エグリンcと呼ばれる阻害剤による滴定で測定した。エグリンc(leech Hirudo medicinalis)は、サブチリシン及びASPプロテアーゼとの相互作用が強いタンパク質阻害剤であり(Heinz et al.,Biochemistry,31:8755~66[1992])、それゆえプロテアーゼ酵素濃度を測定するのに使用することができ、ひいては比活性の算出が可能になる。エグリンc遺伝子を合成し、標準法により大腸菌で発現させた。特性及び阻害強度はSigmaから購入したエグリンcと同様であった。
既知の比活性を有するバチルス・レンタス(Bacillus lentus)のサブチリシンサンプルを、1mMのCaCl2及び0.005% TWEEN(登録商標)-80(トリス/Ca緩衝液)を含有している100mMのトリス緩衝液(pH 8.6)で、上記のAAPFプロテアーゼアッセイに適切な濃度に希釈した。トリス/Ca緩衝液で、エグリンc原液の希釈物もいくつか調製した。各希釈エグリンc溶液のアリコートを、等量の、バチルス・レンタス(Bacillus lentus)の希釈サブチリシン溶液と混合した。エグリンcの非存在下での、阻害されていないサブチリシンの活性を測定するために、エグリンcを不含のトリス/Ca緩衝液のみのアリコートも、等量の、バチルス・レンタス(Bacillus lentus)の希釈サブチリシン溶液と混合した。混合溶液を室温で15~30分インキュベートし、次いで各サンプルのプロテアーゼ活性を上記のAAPFアッセイにより測定した。既知の比活性を有するバチルス・レンタス(Bacillus lentus)のサブチリシンを用いて、各サンプル中の活性プロテアーゼ濃度を測定した。次いで各サンプル中のエグリンc濃度を、トリス/Ca緩衝液のみ(エグリンc不含)と混合した未阻害のサブチリシンサンプルと比較し、観察されるプロテアーゼ活性の減少度に基づいて算出した。したがって、希釈度及び容量が既知のエグリンc溶液を用い、原液中のエグリンcの濃度を測定した。
サブチリシン変異体サンプルを、1mMのCaCl2及び0.005% TWEEN(登録商標)-80(トリス/Ca緩衝液)を含有している100mMのトリス緩衝液(pH 8.6)で希釈した。トリス/Ca緩衝液で、既知の濃度のエグリンc原液の希釈物もいくつか調製した。各希釈エグリンc溶液のアリコートを、等量のサブチリシン変異体溶液と混合した。混合溶液を室温で15~30分インキュベートし、次いで各サンプルのプロテアーゼ活性をAAPFアッセイにより測定した。各エグリンcサンプル及び既知の濃度のエグリンcの添加に基づくプロテアーゼ活性の減少を観察することで、各サブチリシン酵素変異体を完全に阻害するのに必要とされるエグリンc濃度を算出した。この濃度はサンプル中の酵素濃度と等価である。同様に、エグリンcは不含の、トリス/Ca緩衝液のみのアリコートを各サブチリシン変異体サンプルと混合し、エグリンcの非存在下でのプロテアーゼ活性をAAPFアッセイにより測定した。次いでサブチリシン変異体の比活性を、上記のように測定した酵素濃度を用い算出した。
96ウェルのマイクロタイタープレート(MTP;Corning 3641)中に入れる、予洗し、パンチで型通りに切り取り、血液、ミルク及びインク(BMI)により染色した直径5.5ミリメートルのマイクロスウォッチ(EMPA116)を、Center for Testmaterials BV(Vlaardingen,The Netherlands)から得た。
x=(対象ppm)(vb)/(y-対象ppm)
式中、x=酵素量,y=酵素濃度,vb=緩衝液量
Versispan 8チャンネルアームを持つPerkin-Elmer Janusロボットを使用し、コンダクティブチップを用い原液プレート(TCA酵素濃度アッセイで使用し回収した変異体をプールした、Axygenの深さ半分のウェルプレート)から緩衝液を入れた試験プレートへと様々な容量の酵素を分注した。試料を上下に3回ピペッティングして混合した。均等化したプレートのAAPF活性を測定し、母液プレートと比較することで、酵素希釈の正確さを評価し、性格な希釈がなされたか検証した。
代表的なアニオン性界面活性剤(LAS=直鎖アルキルベンゼンスルホン酸塩、ドデシルベンゼン硫酸ナトリウムDOBS)及びEDTA二ナトリウムの存在下でのプロテアーゼ変異体の安定性を、所定の条件下でのインキュベーション後に測定し、かつ上記AAPFアッセイを用いて残効性を測定した。試薬は、ドデシルベンゼンスルホン酸ナトリウム塩(DOBS,Sigma No.D-2525)、TWEEN(登録商標)-80(Sigma No.P-8074)、EDTA二ナトリウム(Siegfried Handel No.164599~02)、HEPES(Sigma No.H-7523)、未負荷緩衝液:50mMのHEPES(11.9g/L)+0.005% TWEEN(登録商標)-80(pH 8.0)、負荷緩衝液:50mMのHEPES(11.9g/L)、0.1%(w/v)DOBS(1g/L)、10mMのEDTA(3.36g/L)(pH 8.0)、参照プロテアーゼ及びプロテアーゼ変異体培養上清(200~400μg/mLのタンパク質を含有)を使用した。装置は、希釈プレートとしてV又はU底MTP(それぞれGreiner 651101及び650161)、未負荷及びLAS/EDTA緩衝液用平底MTP(Corning 9017)、並びにsuc-AAPF-pNAプレート、Biomek FX(Beckman Coulter)、Spectramax Plus 384 MTPリーダー(Molecular Devices)、及びiEMS恒温器/振盪機(1mm振幅)(Thermo Electron Corporation)を使用した。
このアッセイに関し、鶏卵黄を用い、卵黄基材を焼き付けた96ウェルのプレートを調製する。鶏卵黄を白身から取り分け、膜嚢から出し、ミリQ水で20%(体積/重量)に希釈した。希釈した黄身を、電磁撹拌器を用い室温で15分にわたって撹拌する。8チャンネルのピペットを用い、96ウェルのV底プレート(Costar #3894)の各ウェルの中央に、注意深く5μLずつ分取する。プレートを90℃で1時間にわたって焼付け、室温に放冷する。卵黄基材を焼き付けたプレートを室温で保管し、調製後一週間以内に使用した。食洗機用の洗剤を本明細書に記載のように調製し、50℃に予熱する。8チャンネルのピペットを用い、洗剤の190μLのアリコートを96ウェルプレートの各ウェルに加える。96チャンネルのピペット装置を用い、希釈酵素を各ウェルに10μL加える。接着箔シーラーによりプレートを注意深くシーリングし、50℃で30分にわたって振盪した。120μLの反応混合物を新しい96ウェル平底プレートに移し、405nmで吸光度/光散乱を測定した。405nmでの吸光度/光散乱は、卵黄除去性に比例する。
食洗機用の洗剤を本明細書に記載のように調製した。使用機材には、New Brunswick Innova 4230振盪器/恒温器及びSpectraMAX(340型)MTPリーダーが挙げられる。MTPはCostarから得られる(9017型)。色素と混合した卵黄をエージングさせたスウォッチ(CS-38)をCenter for Test Materials(Vlaardingen,Netherlands)から得る。布地は、0.25インチ(0.64cm)の円形のマイクロスウォッチを裁断する前に水で洗浄する。1枚のマイクロスウォッチを96ウェルマイクロタイタープレートの各ウェルに配置する。試験洗剤を50℃で平衡化させる。マイクロスウォッチを含有しているMTPの各ウェルに190μLの洗剤溶液を添加した。この混合物に、10μLの希釈酵素溶液を添加する。MTPを接着ホイルでシーリングし、恒温器に30分間配置してエージングする。インキュベーション後、各ウェルから100μLの溶液を新しいMTPに移す。SpectraMax MTPリーダーを用い、このMTPを405nmで読み取りする。ブランク対照、並びにマイクロスウォッチ及び洗剤を含有しているが酵素は不含の対照も包含させる。
これらの実施例で使用されるステンレス鋼シート(10×15cm;片面をブラシ処理済み)を、市販の高アルカリ性洗剤(例えば、ECOLAB(登録商標)洗剤;Henkel)を用いて研究用食洗機で95℃で十分に洗浄することで、清潔でグリースの除去されたシートを用意する。これらのシートからは初回使用前に反りをとる。卵黄により染みを付ける前にシートを保温キャビネット内で80℃で30分間乾燥させる。染み処理前にはブラシ処理する表面に触れない。また、表面上には水染み又は毛羽立ちを存在させない。冷却したシートは染み処理前に秤量する。
これらの実験では、EN50242、1495型、0219番の直径19cmのデザート皿(Arzberg、白色、施釉磁器)を使用する。合計225gの赤身のブタ及びウシ(半分ずつ)から目に見える脂肪を除去した後、細かくミンチし、冷却する。混合物を2度肉挽き機にかける。温度が35℃を超えて上昇しないようにした。次にひき肉225gを75gの卵(白身及び黄身は混ぜてある)と混合する。調製物は、次に、使用前に-18℃で最大3ヶ月冷凍させる。ブタが利用できない場合にはウシを使用する。
これらの実験で使用したステンレス鋼シート(10×15cm;片面をブラシ処理済み)は、グリースを除去しシートを清潔にするために、市販の高アルカリ性洗剤を用い研究用食洗機で95℃で十分に洗浄する。シートはセルロース性の布で拭いて乾燥させる。染み処理前にはブラシ処理する表面に触れない。また、表面上には水染み又は毛羽立ちを存在させない。染み処理前に80℃の保温キャビネットにシートを30分配置する。冷却したシートは染み処理前に秤量する。
パスタソース(390g)を、ゆでたパスタ・スパゲティ150g、挽肉25g(改良されたIKW組成物-赤身挽肉225g及び卵黄75gの混合物)及びGrozette Formaggioチーズ50gと混ぜる。スプーンを使用して、各白色磁気プレート(Arzberg、19cm直径、白色、施釉磁気、EN 50242、1495型、0219番に一致)に、未汚染の余白を縁に2cm幅で残しつつ混合物を3gずつ塗り広げる。混合物を、オーブンにより120℃で2時間焼き付けて、プレートを乾燥させる。プレートが冷却されたらすぐに使用の準備をする。保管の際、プレートは、各プレートの間に紙タオルを挟んで重ねる。洗浄後、プレートにヨード溶液(0.05N)を吹きつけて炭水化物残留物を識別しやすくする。IKW写真カタログ(IKW)を参照して炭水化物残留物の色反応を視覚的に検査し、0~10の尺度(10が清潔)で採点し、洗浄性能を評価する。
性能指数は、同様のタンパク質濃度下で変異体性能(実測値)と標準酵素性能(理論値)とを比較する。加えて、理論値は、標準プロテアーゼの性能投与応答曲線(performance dose response curve)のパラメーターを用いて算出することができる。
部位評価ライブラリ(SEL)を用いるGG36単独変異体の生成
本実施例に記載のGG36 SELの構築は、その適切な方法、並びに遺伝子最適化、遺伝子合成、ライブラリ作成、及び解析のための技術基盤を用いGENEARTにより実施された(国際公開第2004/059556(A3)号、欧州特許番号第0 200 362号及び同第0 201 184号、並びに米国特許第4,683,195号、同第4,683,202号及び同第6,472,184号)。GG36 SELは、B.サブチリス発現プラスミドpHPLT-GG36(図2を参照)を用い、本発明者らにより予め選択された位置で製造した。このB.サブチリスの発現プラスミドは、以下に示すGG36発現カセットを含有するものである:B.リケニフォルミス(B.licheniformis)のLATプロモーター(Plat)、並びにレプリカーゼ遺伝子(reppUB)、ネオマイシン/カナマイシン耐性遺伝子(neo)及びブレオマイシン耐性マーカー(bleo)が挙げられる、pUB110由来の更なる要素(McKenzie et al.,Plasmid,15:93~103,1986)(米国特許第6,566,112号、図4を参照)。pHPLT-GG36プラスミドマップを図2に提供する。GG36発現カセット配列は以下に提供されるものである。
GG36変異体のNHJ1及びWCE1のセットの構築及びクリーニング性能
本明細書に記載の、上記のB.サブチリス発現プラスミドpHPLT-GG36(図2)を用い、GG36変異体のNHJ1及びWCE1セットをDNA 2.0で構築した。変異体を実施例2に記載のようにB.サブチリス細胞で発現させ(遺伝子型:ΔaprE,ΔnprE,amyE::xylRPxylAcomK-phleo)、更に、タンパク質含量を測定するためのTCAアッセイ、LAS/EDTA安定性アッセイ、及び実施例1に記載のようなBMIマイクロスウォッチクリーニングアッセイを用いて特徴付けした。結果を表3-1及び3-2に示す。以降の表中で、洗剤組成物(「Det」)は、上記表Dに示されるものと対応する。同様に、記載のように、アミノ酸位置はBPN’の番号付けに対応させて列挙される。
GG36変異体のNHJ4セットの構築及びクリーニング性能
下表4-4に記載のGG36変異体のNHJ4セットを、以下に記載するように、融合PCR又はQUIKCHANGE(登録商標)多部位特異的変異キット(「QCMSキット」、Stratagene)を使用し、B.サブチリス発現プラスミドpHPLT-GG36(図2)を用い構築した。
QUIKCHANGE(登録商標)多部位特異的変異誘導を用いて生成した変異体を表4-4に示す。製造元からの取扱説明書に従って、2マイクログラムのDNA及びDamメチラーゼ(NEB)を用い、親プラスミドpHPLT-GG36(テンプレートDNA)をメチル化した。製造元のプロトコールに従い、QuikChange(登録商標)多部位特異的変異導入キット(「QCMS kit」;Stratagene)を用い部位特異的変異を導入した(プライマー配列に関しては表4-1を参照されたい)。B.サブチリスを効率的に形質転換させるために、Illustra Templiphiキット(GE Healthcare)を用い、反応を製造元のプロトコールに従い実施し、QCMS反応混合液中のDNAをローリングサークル型増幅(RCA)により増幅させた。1マイクロリットルの、10倍希釈した増幅DNAを使用して、コンピテントなB.サブチリス(B.subtilis)細胞(遺伝子型:ΔaprE,ΔnprE,amyE::xylRPxylAcomK-phleo)50μLを形質転換させた。形質転換混合物を37℃にて1時間にわたって振盪した。形質転換混合物の10マイクロリットルアリコートを、10μg/mLのネオマイシン(Teknova)を添加したスキムミルク(1.6%)Luria寒天プレートに蒔いた。続いて、スキムミルクプレート上で透明な領域(ハロ)を生じたコロニーを、プラスミドDNAの抽出(QIAprep Spin Miniprepキット,Qiagen)用に10μg/mLのネオマイシンを含有している120μLのLB培地に接種した。抽出したプラスミドを、配列決定して、所望の変異が存在しているか確認した。
伸長PCRにより、GG36のコンビナトリアルな変異体を10種作成した。pHPLT-GG36プラスミドに導入した変異及びこの目的で使用したプライマーの一覧を表4-2に示す。各変異を作成するために、表4-2に示すプライマーを用いいくつかの断片(表4-3)を増幅させた。各PCR増幅反応物には、30pmolの各プライマー及び100ngのDNAテンプレート、pHPLT-GG36プラスミドを含有させた。増幅はVent DNAポリメラーゼ(NEB)を用いて実施した。PCR反応(20μL)は、まず始めに95℃で2.5分加熱した後、続いて94℃で15秒の変性、55℃で15秒のアニーリング、及び72℃で2分の伸長を30サイクル行った。増幅させた後、各変異体につき2~4つのPCRフラグメント(表4-3)をQIAGEN(登録商標)ゲルバンド精製用キットを用いゲルから精製し、混合した(各フラグメントにつき50ng)。完全長の遺伝子フラグメントを生成するためにプライマーP5954及びP5955を用い伸長PCRする際、これらの混合物をDNAテンプレートとして使用した。伸長工程を72℃で2分にわたって実施したことを除き、PCR条件は上記の条件と同様のものであった。完全長のDNAフラグメントをQIAGEN(登録商標)ゲルバンド精製用キットを用いてゲルから精製し、制限酵素BamHI及びHindIIIを用いて消化し、同様の制限酵素で消化したpHPLT-GG36でライゲーションした。Illustra Templiphiキットでローリングサークル型増幅法を用い、1マイクロリットルのライゲーション混合物を製造元(GE Healthcare)からの取扱説明書に従って増幅させることで、バチルス・サブチルスに形質転換させるための多量体DNAを生成した。ローリングサークル型増幅産物を100倍希釈し、B.サブチリス細胞の形質転換に用いた(遺伝子型:ΔaprE,ΔnprE,amyE::xylRPxylAcomK-phleo)。形質転換混合物のアリコートを、1.6%のスキムミルク及び10μg/mLのネオマイシンを含有しているLBプレートに蒔き、37℃で一晩インキュベートした。続いて、ハローを生じたコロニーを、プラスミドDNAを抽出するため(QIAprep Spinミニプレップキット、Qiagen)10μg/mLのネオマイシンを含有している120μLのルリアブロス培地に接種した。抽出したプラスミドを、配列決定して、所望の変異が存在しているか確認した。表4-4に示される伸長PCRによる変異体生成。
GG36変異体のNHJ3セットの構築及びクリーニング性能
本明細書に記載の変異体のNHJ3セットは、次の変異:S101G、S103A、V104I、G159D、A232V、Q236H、Q245R、N248D、及びN252K(BPN’番号に対応)、を含有しているGG36変異体(GG36-9として参照)に基づくものである。これらの変異は、DNAテンプレートとしてpRA68プラスミド(図3を参照)を使用し、部位特異的な変異導入キットQUIKCHANGE(登録商標)Lightning(QCLDSキット、Stratagene)を用いることで生成した。プラスミドpRA68は、pBN3ベクター(Babe et al.,Biotech.Appl.Biochem.27:117~124[1998]を参照)から誘導した。
GG36変異体のNHJ5セットの構築及びクリーニング性能
本明細書に記載の変異体のNHJ5セットは、次の変異:S101G、S103A、V104I、G159D、A232V、Q245R、N248D及び(BPN’番号に対応)、を含有しているGG36変異体(GG36-7として参照)に基づくものである。pRA96プラスミド(図4を参照)をDNAテンプレートとして使用し、部位特異的な変異導入キットQUIKCHANGE(登録商標)を用いることで、これらの変異を生成した。組み込んだ変異、及び変異をGG36-7に組み込むのに使用したプライマー配列を表6-1に示す。実施例4に記載の方法を用い、変異体を作製した。エグリンc阻害アッセイ(実施例1)及びBMIマイクロスウォッチクリーニングアッセイ(実施例1)を用いタンパク質含量を決定するなどといった、更なる生化学的解析を行うため、実施例2に記載のようにB.サブチリス変異体株を増殖させた。結果を下表6-2に提供する。PI値はGG36に対するものである。以降の表中で、洗剤組成物(「Det」)は、上記表Dに示されるものと対応する。同様に、記載のように、アミノ酸位置はBPN’の番号付けに対応させて列挙される。
NHJ2コンビナトリアルライブラリの構築
本実施例は、次の変異:A16S、T22A、S101A、S103G、V104L、L111V、S128N、及びL148I(BPN’番号に対応)を1つ以上包含するGG36コンビナトリアルライブラリの構築について記載する。NHJ2コンビナトリアルライブラリの作成のため、B.サブチリス発現プラスミドpHPLT-GG36をDNA 2.0 Inc.に提供した。B.サブチリス株(遺伝子型:ΔaprE,ΔnprE,amyE::xylRPxylAcomK-phleo)で形質転換するために、構築済みのNHJ2ライブラリのライゲーション反応物が、DNA 2.0,Inc.から提供された。作製した変異体は、本明細書で記載の変異を1つ又は複数含有しており、本明細書に記載の方法及び洗剤組成物を用い冷水用途に関し試験することができる。
更なるライブラリ及びGG36変異体の構築
次の変異セット:A1R、A230E、E271L、G115R、G20R、H249R、K235F、K27V/F/L、L75E、L82R、N18R、N269R、N43D、N43R、N76D、R45T、S212F、S242R、S24R、S78R、S9A、T22R、V121E、V244R、V28E、V30E、V4R、W241R(BPN’番号に対応)を用い、更なるライブラリ及び変異体を構築する。DNA 2.0,Inc.に外注し、B.サブチリスの発現プラスミドpHPLT-GG36を使用してライブラリ及び変異体を作製した。ライブラリ又は変異体のライゲーション反応物でB.サブチリス株を形質転換させた(遺伝子型:ΔaprE,ΔnprE,amyE::xylRPxylAcomK-phleo)。作製された変異体はこれらの変異を1つ以上含有している。この変異体を、本明細書に記載の方法及び洗剤組成物を用いBMIマイクロスウォッチクリーニングアッセイ(実施例1)で冷水クリーニングについて試験した。結果を下表8-1に提供する。以降の表中で、洗剤組成物(「Det.」)は、上記表1-2に示されるものと対応する。同様に、記載のように、アミノ酸位置はBPN’の番号付けに対応させて列挙される。
GG36ライブラリWCE2の構築及びクリーニング性能
B.サブチリス発現プラスミドpHPLT-GG36を用い、DNA 2.0,Inc.によりWCE2コンビナトリアルライブラリを生成した。構築したWCE2ライブラリのライゲーション反応物でB.サブチリス株を形質転換させた(遺伝子型:ΔaprE,ΔnprE,amyE::xylRPxylAcomK-phleo)。WCE2ライブラリの生成に使用される変異セットは、A230E、G20R、H249R、N18R、N43R/D、N76D、R45T、S242R、及びS24R(BPN’番号に対応)である。作製された変異体はこれらの変異を1つ以上含有しており、この変異体を、本明細書に記載の方法及び洗剤組成物を用いBMIマイクロスウォッチクリーニングアッセイ(実施例1)で冷水クリーニングについて試験する。結果を下表9-1に提供する。以降の表中で、洗剤組成物(「Det.」)は、上記表1-2に示されるものと対応する。同様に、記載のように、アミノ酸位置はBPN’の番号付けに対応させて列挙される。
GG36変異体のWCE3セットの構築及びクリーニング性能
本実施例は、GG36変異体、GG36-7(実施例5)及びGG36-9(実施例4)に基づく変異のWCE3セットを記載する。これらの変異は:S101G-S103A-V104I-A232V-Q245R-N248D、S101G-S103A-V104I-G159D-A232V-Q245R、S101G-S103A-V104I-G159R-A232V-Q245R-N248D、S101G-S103A-V104I-G159D-A232V-Q245R-N248R、S101G-S103A-V104I-A232V-Q245R、S101G-S103A-V104I-A232V-Q245R-N248R、S101G-S103A-V104I-G159R-A232V-Q245R-N248R、並びにS101G、S103A、V104I、A232V、Q236H、Q245R、及びN252Kである。実施例5に記載のように、DNAテンプレートとしてpRA96プラスミドを使用し、QuikChange(登録商標)Lightning多部位特異的変異誘導キット(QCLMSキット、Stratagene)を用いることで、これらの変異体を生成した。作製された変異体を、表1-2に記載の洗剤を用い、BMIマイクロスウォッチアッセイ(実施例1)で冷水クリーニングについて試験した。
GG36の更なるライブラリ及び変異体の構築
実施例は、GG36変異体の構築、及びB.サブチリス発現プラスミド(例えば、pHPLT-GG36、図2)を用い、次の変異:A16S、T22A、S24R、N62E、N76D、E89P、S101A/G、S103G/A、V104L/I、L111V、S128N、P129E、A232V、L148I、A158E、G159D/E、S166D、R186H、S188D、Y209E、Q236H、N238R、Q245R、N248D/R、H249R、N252K/R、T253R、E271F(BPN’番号に対応)を1つ以上使用するライブラリを記載する。DNA 2.0,Inc.に外注し、B.サブチリス発現プラスミド(例えば、pHPLT-GG36;図2)発現プラスミド及びB.サブチリス株(遺伝型:ΔaprE,ΔnprE,amyE::xylRPxylAcomK-phleo)を用い、コンビナトリアルな変異体を構築した。DNAライブラリに関して言えば、B.サブチリス発現ベクター(例えば、pHPLT-GG36;図2)を用い構築した各ライブラリのライゲーション反応物でB.サブチリス株(遺伝子型:ΔaprE,ΔnprE,amyE::xylRPxylAcomK-phleo)を形質転換させた。生成した変異体は上記の変異を1つ以上含有するものであり、この変異体を、表1-2に記載の洗剤組成物を用いBMIマイクロスウォッチアッセイ(実施例1)で冷水クリーニングについて試験した。
GG36の更なるライブラリ及び変異体の構築
本実施例は、GG36変異体及び次の変異(BPN’番号付け)を1つ以上用いるB.サブチリスライブラリの構築について記載する:A1R、Q2S、Q2M、Q2A、Q2R、Q2W、S3R、V4R、V4S、V4C、I8A、S9A、S9F、S9W、R10S、R10A、R10H、R10M、Q12F、Q12R、P14K、P14F、P14Q、A15R、A15F、A16S、H17R、H17M、H17F、N18R、N18K、G20F、G20K、G20R、T22A、T22R、T22Y、T22V、T22Q、T22L、T22W、G23A、G23S、G23F、S24R、S24F、S24W、S24Q、S24H、S24L、G25V、G25F、G25R、V26F、K27L、K27F、K27R、K27V、V28A、V28N、V28E、A29T、V30E、L31F、T33S、T33G、T33D、G34P、I35M、S36T、S36F、S36R、T38L、T38F、T38R、P40N、P40L、P40T、P40W、P40H、P40R、L42I、N43A、N43F、N43I、N43S、N43R、N43M、N43W、N43D、R45T、G46R、A48R、F50C、V51W、V51F、V51H、P52F、P52E、P52N、P55Y、T57R、Q59A、Q59F、Q59R、D60P、D60Q、D60A、N62E、N62Q、G63V、G63M、G63T、G63I、G63A、G63S、G63H、G63Q、G63D、G63E、G63P、H64F、H64T、V68A、V68C、A69N、A69T、A69P、A69W、T71G、I72C、A74C、L75A、L75F、L75E、L75R、N76D、S78R、S78N、S78I、I79W、I79Q、V81R、L82F、L82T、L82V、L82R、L82M、A85M、P86W、P86L、P86I、E89P、E89T、E89G、E89H、E89L、E89V、E89W、E89F、E89I、Y91N、Y91F、A92F、K94N、S99F、S99T、S99P、S99G、S99M、G100S、G100N、G100Q、G100I、S101A、S101N、S101G、S101T、S101D、S101E、S101P、S101F、G102A、G102T、G102N、G102H、G102E、S103G、S103N、S103D、S103A、V104L、V104I、V104E、V104D、S105T、S105E、S105Q、S106G、S106T、S106E、S106D、S106A、S106V、S106F、I107M、I107F、A108I、A108G、Q109M、L111V、L111I、E112V、E112L、E112Q、A114G、G115K、G115R、N116K、N116A、N116L、N117F、G118R、G118I、M119C、H120A、H120F、H120R、V121F、V121E、N123G、N123E、L124S、S128D、S128F、S128L、S128N、S128H、S128M、S128I、S128Q、P129E、S132A、S132E、A138G、S144R、V147L、L148I、A158E、G159D、G159E、G159C、S160D、S166D、S166E、Y167W、M175V、V177C、D181A、Q182R、N183I、N183D、N183M、N183F、N183R、N185E、N185V、N185I、R186H、R186K、S188E、S188D、S188R、Y192H、Y192W、A194E、A194V、A194F、D197F、I198L、I198F、V203E、V203C、T208S、Y209S、Y209N、Y209F、Y209T、Y209E、Y209H、Y209G、Y209L、P210R、P210V、P210L、G211Q、G211R、S212I、S212M、S212F、T213A、Y214F、A215N、A215D、A215E、A215H、A215F、S216F、S216A、L217E、L217N、L217D、N218D、N218P、N218E、T224A、T224G、V227I、A230E、A231I、A231C、A232V、L233C、V234F、K235F、Q236F、Q236N、Q236H、N238R、N238K、N238L、P239K、P239G、P239R、P239H、P239T、P239N、P239S、P239F、S240R、W241R、S242L、S242R、N243F、N243R、V244R、Q245R、I246S、N248D、N248V、N248I、N248R、H249R、H249T、L250I、K251R、K251S、N252I、N252F、N252R、N252K、N252H、T253I、T253R、T253F、A254C、S256N、G258R、T260V、T260I、L262D、L262H、Y263F、S265F、L267V、L267N、L267M、N269I、N269R、A270C、E271I、E271V、E271H、E271M、E271L、E271P、E271A、E271F、E271T、A272F、A272F、A272R、A273F、A273I、及びT274G。変異体及びライブラリは実施例11に記載のようにDNA 2.0,Inc.に外注し構築した。作製された変異体はこれらの変異を1つ以上含有しており、この変異体を、BMIマイクロスウォッチクリーニングアッセイ(実施例1)及び表1-2に記載の洗剤組成物で冷水クリーニングについて試験した。
GG36の更なるライブラリ及び変異体の構築
本例は、追加のGG36変異体、及びB.サブチリスで構築されたライブラリを用いる冷水クリーニングについて記載する。ほとんどのDNAライブラリはDNA 2.0,Inc.に外注してB.サブチリス発現プラスミドpHPLT-GG36を用い構築した。実施例4に記載されるようなローリングサークル型増幅によりDNAを増幅した後、構築したライブラリのライゲーション反応物を用い、B.サブチリス株(遺伝子型:ΔaprE,ΔnprE,amyE::xylRPxylAcomK-phleo)を形質転換した。伸長PCR又はQuickChange変異導入によりWCE9及びNHJ10ライブラリ及び変異体を作製した(方法に関する記載については実施例4を参照されたい)。また、B.サブチリス発現プラスミドpHPLT-GG36を用い、WCE9及びNHJ10ライブラリ及び変異体を作製した。変異体を実施例1に記載のようにB.サブチリス細胞(遺伝子型:ΔaprE,ΔnprE,amyE::xylRPxylAcomK-phleo)で発現させ、かつ更に、実施例1に記載のようなBMIマイクロスウォッチクリーニングアッセイを用いて特徴付けした。以降の表中で、洗剤組成物(「Det.」)は、上記表1-2に示されるものと対応する。同様に、記載のように、アミノ酸位置はBPN’の番号付けに対応させて列挙される。
粒状及び/又は錠剤型洗濯用組成物
本例は、粒状及び/又は錠剤型洗濯洗剤に関する様々な配合を提供する。粒状又は錠剤型であり得る本発明の洗濯組成物を以降に提供する。これらの配合物のそれぞれにおいて、本明細書で提供される少なくとも1種のプロテアーゼ変異体は、約0.0001~約10重量%の濃度で含有される。一部の代替的な実施形態では、配合者による判断のもと、必要に応じて他の濃度が使用され得る。
錠剤型洗剤組成物
本実施例は、錠剤型洗剤組成物に関する様々な配合を提供する。標準的な12ヘッド式ロータリープレスを用い、粒状食器洗浄洗剤組成物を13KN/cm2の圧力で圧縮することで、以下の本発明の錠剤型洗剤組成物を調製する。これらの配合物のそれぞれにおいて、本明細書で提供される少なくとも1種のプロテアーゼ変異体は、約0.0001~約10重量%の濃度で含有される。一部の代替的な実施形態では、配合者による判断のもと、必要に応じて他の濃度が使用され得る。
液体洗濯洗剤組成物
本例では、様々な配合の液体洗濯洗剤組成物を提供する。次の本発明の液体洗濯洗剤組成物を以下に示すように調製する。これらの配合物のそれぞれにおいて、本明細書で提供される少なくとも1種のプロテアーゼ変異体は、約0.0001~約10重量%の濃度で含有される。一部の代替的な実施形態では、配合者による判断のもと、必要に応じて他の濃度が使用され得る。
食器手洗い用液体洗剤組成物
この実施例では、様々な食器手洗い用液体洗剤配合物が提供される。以降、本発明の手洗い用液体洗剤組成物が提供される。これらの配合物のそれぞれにおいて、本明細書で提供される少なくとも1種のプロテアーゼ変異体は、約0.0001~約10重量%の濃度で含有される。一部の代替的な実施形態では、配合者による判断のもと、必要に応じて他の濃度が使用され得る。
自動食器洗浄機用液体洗剤組成物
この実施例では、様々な、食器自動洗浄機用液体洗剤配合物が提供される。以降、本発明の手洗い用液体洗剤組成物が提供される。これらの配合物のそれぞれにおいて、本明細書で提供される少なくとも1種のプロテアーゼ変異体は、約0.0001~約10重量%の濃度で含有される。一部の代替的な実施形態では、配合者による判断のもと、必要に応じて他の濃度が使用され得る。
高密度食器洗浄洗剤
本例は高密度食器洗浄洗剤の様々な配合を提供する。本発明のコンパクト高密度食器洗浄洗剤を以降に提供する。これらの配合物のそれぞれにおいて、本明細書で提供される少なくとも1種のプロテアーゼ変異体は、約0.0001~約10重量%の濃度で含有される。一部の代替的な実施形態では、配合者による判断のもと、必要に応じて他の濃度が使用され得る。
液体硬質表面クリーニング洗剤
本例は、液体硬質表面クリーニング洗剤の様々な配合を提供する。本発明の液体硬質表面クリーニング洗剤組成物を以降に提供する。これらの配合物のそれぞれにおいて、本明細書で提供される少なくとも1種のプロテアーゼ変異体は、約0.0001~約10重量%の濃度で含有される。一部の代替的な実施形態では、配合者による判断のもと、必要に応じて他の濃度が使用され得る。
自動食器洗浄性能試験
本例では、市販の一部の食器洗浄用洗剤を用いプロテアーゼ変異体の洗浄性能を測定するために使用される方法について記載する。プロテアーゼ変異体は様々な条件下で試験する。これらの洗剤はWFKから市販されるものであり、以下に指定することで参照される。各種類の染み(挽肉、卵黄、及び卵黄とミルク)を以下に提供する。試験皿は、個々の種類の染みをに塗布する前にしっかりと洗浄すべきである。試験前から皿表面にある種のしつこい染みが残っている場合もあることから、皿を十分に洗浄しておくことは特に不可欠である。新しい皿は試験の初回に使用する前にも3回しっかりと洗浄した。
Claims (5)
- 単離されたサブチリシン変異体であって、
前記サブチリシン変異体が、タンパク質分解活性を有する成熟型であり、かつG020R-N043Rを含むアミノ酸置換の組み合わせを含み、
前記G020R-N043Rを含むアミノ酸置換の組み合わせは、G020R-N043R-A230E, G020R-N043R-A230E-S242R, G020R-N043R-E271L, G020R-N043R-H249R-E271L, G020R-N043R-N269R, G020R-N043R-R045T-A230E, G020R-N043R-R045T-S101A-N269R, G020R-N043R-R045T-S242R, G020R-N043R-S101A-N116A-T213A-A215F, G020R-N043R-S101A-N269R, G020R-N043R-S212F, G020R-N043R-S212F-W241R, G020R-N043R-S242R, G020R-N043R-S242R-E271L, G020R-N043R-S242R-H249R, G020R-N043R-V244R, G020R-N043R-W241R, G020R-S024R-N043R-R045T-H249R, G020R-S024R-N043R-R045T-N116A, G020R-S024R-N043R-R045T-N116A-T213A, G020R-S024R-N043R-R045T-S101A-T213A, G020R-S024R-N043R-S242R, G020R-T038A-N043R-S101A, N018R-G020R-N043R-N076D-S242R-H249R, N018R-G020R-N043R-R045T-S242R, S009A-G020R-N043R-S212F, S009A-G020R-N043R-W241R, S009A-G020R-S024R-N043R, V004R-G020R-N043R, V004R-G020R-S024R-N043R, V004R-G020R-S024R-N043R-S242R, V004R-S009A-G020R-N043R-S242R, G020R-N043R-N076D, N018R-G020R-N043R, G020R-S024R-T38I-N043R-R045T-N076D-S242R-H249R, G020R-N043R-N076D-A230E-H249R, N018R-G020R-N043R-N076D, N018R-G020R-N043R-R045T-N076D-H249R, G020R-S024R-N043R-N076D, G020R-S024R-N043R-R045T-A215F, N018R-G020R-N043R-N076D-A230E-S242R, N018R-G020R-S024R-N043R-N076D-H249R, V004R-S009A-G020R-N043R, G020R-T022R-N043R, G020R-T022R-N043R-W241R, G020R-T022R-N043R-S212F, G20R-S024R-K027E-N043R-N076D-A230E,N018R-G020R-S024R-N043R-R045T-N076D-A230E, N018R-G020R-N043R-N076D-H249R, G020R-N043R-S101G-S103A-V104I-A232V-Q245R, G020R-S024R-N043R-R045T, G020R-S024R-N043R-R045T-S101A-N269R, P014L-G020R-S024R-N043R-R045T-S101A-A215F, G020R-S024R-N043R-R045T-N076D-S242R-H249R, G020R-N043R-N076D-S101G-S103A-V104I-A232V-Q245R-N269R, N018R-G020R-N043R-R045T-N076D-S101G-S103A-V104I-A232V-Q245R, G020R-S024R-N043R-R045T-N116A-T213A-A215Fであり、
前記変異体が、親プロテアーゼである、配列番号2で示されるアミノ酸配列を含むバチルス・レンタス(Bacillus lentus)のサブチリシンGG36プロテアーゼの変異体であり、
前記変異体が、配列番号2のアミノ酸配列に対し、少なくとも90%の配列同一性を有し、
前記プロテアーゼ変異体のアミノ酸位置が、配列番号1で示されるバチルス・アミロリケファシエンス(Bacillus amyloliquefaciens)のサブチリシンBPN’のアミノ酸配列の、対応するアミノ酸位置に割り振られた番号に従って番号付けされ、そして
前記変異体が、表Fに示された36h、36i、表Gに示された36k、36l、36m、36nのいずれかの洗剤組成物と、0.1~5ppmの酵素を用い、表1-2に示された条件を採用して、16℃で実施されたBMIマイクロスウォッチアッセイで、配列番号2のアミノ酸配列を有する前記サブチリシンGG36プロテアーゼに対する性能指数PIが1.3以上のものである、サブチリシン変異体。 - 請求項1に記載のサブチリシン変異体をコードするポリヌクレオチド配列からなる、単離された核酸。
- 請求項2に記載の核酸を含む、発現ベクター。
- 請求項3に記載の発現ベクターを含む、宿主細胞。
- バチルスサブチリシンの少なくとも1種のサブチリシン変異体を生産する方法であって、
a)請求項1に記載のサブチリシン変異体を少なくとも1種コードする少なくとも1種の核酸を含む発現ベクターにより、宿主細胞を形質転換させることで、形質転換された宿主細胞を生産する工程、
b)前記形質転換された宿主細胞を、少なくとも1種のサブチリシン変異体を生産するのに好適な条件下で培養して、少なくとも1種のサブチリシン変異体を生産する工程、及び
c)生産された前記サブチリシン変異体を回収する工程
を含む、方法。
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