JP2018078904A - 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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- JP2018078904A JP2018078904A JP2018005572A JP2018005572A JP2018078904A JP 2018078904 A JP2018078904 A JP 2018078904A JP 2018005572 A JP2018005572 A JP 2018005572A JP 2018005572 A JP2018005572 A JP 2018005572A JP 2018078904 A JP2018078904 A JP 2018078904A
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- amino acid
- subtilisin
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- acid sequence
- protease
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- 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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- 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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- 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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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
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Abstract
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
1A−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
−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−G020R−T022W−S024R−N076D−S101A−G211Q−T213A−A215F−H249R、A016T−N043R−R045T−N076D−S101G−S103A−V104I−A232V−Q245R−N269R、N018R−T
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−N116A−N183D−T213A−H249R、N018R−S024R−N076D−N116A−A150T−T213A−H249R、N018R−S024R−N076D−N183D−T213A−H249R、N018R−G020R−S024R−N076
D−N116A−N183D−G211Q−A215F−H249R、N018R−G020R−S024R−N076D−G211Q−H249R、N018R−S024R−N076D−S101A−N116A−N183D−I198L−H249R、S024R−N076D−A232V−H249R、N018R−G020R−T022W−S024R−N076D−S101A−N116A−N183D−I198L−G211Q−T213A−H249R、N018R−T022W−S024R−N076D−S101A−N116T−I198L−A215F−H249R、N018R−S024R−N076D−N183D−I198L−G211Q−A215F−H249R、N018R−T022R−S024R−N076D−S101A−N116A−N183D−G211Q−H249R、R045T−S101G−S103A−V104I−A232V−Q245R、N018R−G020R−S024R−N076D−S101A−N183D−G211Q−H249R、G020R−S101G−S103A−V104I−N116A−N183D−T213A−A232V−Q245R、N076D−S101G−S103A−Q245R、G020R−N043D−S078R−S101G−S103A−V104I−A232V−Q245R−H249R、N018R−S024R−N076D−N116A−N183D−H249R、N018R−S024R−N076D−S101A−N183D−G211Q−T213A−A215F−H249R、N018R−G020R−T022W−S024R−N076D−S101A−N116A−I198L−H249R、N018R−T22W−S024R−N076D−G211Q−T213A−H249R、N018R−G020R−S024R−N076D−N183D−G211Q−H249R、N018R−G020R−S024R−N076D−S101A−N116A−N183D−T213A−H249R、N043R−S078R−S101G−S103A−V104I−L217E−A232V−Q245R、N018R−T022W−S024R−N076D−S101A−A215F−H249R、N018R−G020R−S024R−N076D−S101A−N183D−I198L−G211Q−T213A−H249R、N076D−S101G−V104I−H249R、N018R−T022W−S024R−N076D−S101A−N116A−N183D−T213A−H249R、N018R−S024R−N076D−N183D−H249R、N018R−S024R−N076D−S101A−N183D−I198L−A215F−H249R、N018R−T022W−S024R−N076D−N183D−I198L−A215F−H249R、N018R−T022W−S024R−N076D−S101A−I198L−G211Q−H249R、G020R−S101A−S103A−V104I−N116A−N183D−A232V−Q245R、N018R−S024R−N076D−N116A−N183D−I198L−G211Q−H249R、N018R−G020R−S024R−S101G−S103A−V104I−A232V−Q245R、N018R−N076D−S078R−S101G−S103A−V104I−L217E−A232V−Q245R、G020R−S101A−S103A−V104I−N116A−N183D−G211Q−A232V−Q245R、N018R−T022W−S024R−N076D−S101A−N183D−I198L−Y209H−H249R、N018R−S024R−N076D−N183D−I198L−T213A−A215F−H249R、N018R−S024R−N076D−S101A−N116A−N183D−G211Q−T213A−H249R、N018R−T022W−S024R−N076D−S101A−N116A−N183D−G211Q−T213A−H249R、N018R−S024R−N076D−N183D−I198L−H249R、N018R−S024R−N076D−N183D−A215F−H249R、N018R−G020R−S024R−N076D−G211Q−T213A−A215F−H249R、N076D−Q245R、N076D−S101G−V104I−Q245R、N018R−T022W−S024R−N076D−S101A−G211Q−A215F−H249R、N018R−T022W−S024R−N076D−S101A−N116A−N183D−G211Q−A215F−H249R、N018R−G020R−T022W−S024R−N076D−S101A−G211Q−T213A−H249R、G020R−S024R−N043R−S101G−S103A−V104I−A232V−Q245R、N018R−S024R−N076D−N116A−N183D−G211Q−A215F−H249R、G020R−S101A−S103A−V104I−N116A−N183D−T213A−A215F−A232V−Q245R、S101G−S103A−V104I、N018R−G020R−S024R−N076D−S101A−N116A−N183D−G211Q−T213A−H249R、N018R−G020R−S024R−N076D−N204D−T213A−H249R、N018R−T022W−S024R−N076D−N183D−I198L−H249R、N018R−S024R−N076D−S101A−N116A−N183D−A215F−H249R、N018R−T022W−S024R−N076D−N116A−N183D−I198L−G211Q−T213A−A209V−H249R、N018R−T022W−S024R−N076D−S101A−N116A−N183D−G211Q−T213A−A215F−H249R、N018R−S024R−N076D−S101A−N116A−I198L−T213A−H249R、N018R−G020R−S024R−N076D−S101A−N116A−G211Q−T213A−H249R、N018R−G020R−T022W−S024R−N076D−S101A−N116A−N183D−G211Q−T213A−A215F−H249R、N018R−S024R−N076D−S101A−N116A−N183D−T213A−A215F−H249R、N018R−S024R−N076D−S101A−N183D−I198L−G211Q−T213A−A215F−H249R、N018R−S024R−N076D−S101A−N183D−I198L−G211Q−T213A−H249R、N018R−N043R−R045T−S078R−S101G−S103A−V104I−L217E−A232V−Q245R、N018R−S024R−N076D−N183D−G211Q−T213A−A215F−H249R、N018R−T022W−S024R−N076D−N116A−N183D−I198L−A215F−H249R、N018R−G020R−S024R−N076D−N116A−H249R、N018R−G020R−T022W−S024R−N076D−S101A−G211Q−A215F−H249R、N018R−G020R−S024R−N076D−N183D−G211Q−T213A−A215F−H249R、N018R−G020R−T022W−S024R−N076D−I198L−T213A−H249R、N018R−G020R−S024R−N076D−S101A−G211Q−A215F−H249R−N269D、N018R−G020R−N043D−S101G−S103A−V104I−A232V−Q245R−N269R、N018R−T022W−S024R−N076D−S101A−N183D−I198L−T213A−H249R、G020R−T022W−S101G−S103A−V104I−N183D−A215F−A232V−Q245R、N018R−T022W−S024R−N076D−N116A−N183D−I198L−Y209H−G211Q−H249R、N018R−G020R−T022W−S024R−N076D−S101A−N116A−N183D−G211Q−H249R、N076D−A232V−Q245R、N043D−R045T−S078R−S101G−S103A−V104I−A232V−Q245R、N018R−G020R−S024R−N076D−N116A−I198L−G211Q−A215F−Q245R、N018R−G020R−T022W−S024R−N076D−T213A−H249R、G020R−S024R−N043D−S078R−S101G−S103A−V104I−A232V−Q245R−H249R、N018R−G020R−T022W−S024R−N076D−S101A−I198L−A215F−H249R、G020R−A090S−S101G−S103A−V104I−N116A−N183D−T213A−A215F−A232V−Q245R、N018R−G020R−T022W−S024R−N076D−S101A−I198L−G211Q−T213A−A215F−H249R、N018R−G020R−S024R−N076D−S101A−N183D−T213A−A215F−H249R、N018R−S024R−N076D−N116A−N183D−I198L−G211Q−T213A−H249R、N043D−R045T−S078R−S101G−S103A−V104I−A232V−Q245R−N269R、N018R−S024R−N076D−S101A−N183D−A215F−H249R、N018R−G020R−S024R−N076D−S101A−N183D−I198L−T213A−H249R、G020R−T022W−S101A−S103A−V104I−N116A−N183D−I198L−G211Q−T213A−A215F−A232V−Q245R、N018R−G020R−S024R−N043D−N076D−S101G−S103A−V104I−A232V−Q245R−N269R、N018R−S024R−N076D−S101A−N183D−T213A−A215F−H249R、N018R−G020R−T022W−S024R−N076D−S101A−N116A−I198L−G211Q−T213A−A215F−H249R、N018R−G020R−N043D−S101G−S103A−V104I−L217E−A232V−Q245R、N076D−S103A−V104I−A232V−Q245R、R045T−N076D−S078R−S101G−S103A−V104I−A232V−Q245R−H249R、N018R−T022W−S024R−N076D−S101A−N183D−G211Q−A215F−H249R、N018R−T022W−S024R−N076D−S101A−N116A−N183D−H249R、N018R−S024R−N076D−N116A−N183D−I198L−G211Q−A215F−H249R、N018R−G020R−N043D−N076D−S078R−S101G−S103A−V104I−L217E−A232V−Q245R、N076D−S103A−V104I−Q245R、N018R−G020R−S024R−N076D−S101A−N116A−G211Q−T213A−A215F−H249R、N018R−S024R−N076D−S101A−N183D−I198L−H249R、N018R−T022W−S024R−N076D−N116A−N183D−I198L−G211Q−A215F−H249R、N018R−S024R−N076D−N116A−N183D−T213A−A215F−H249R、N018R−T022W−S0
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。
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
1A−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
−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−G020R−T022W−S024R−N076D−S101A−G211Q−T213A−A215F−H249R、A016T−N043R−R045T−N076D−S101G−S103A−V104I−A232V−Q245R−N269R、N018R−T
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−N116A−N183D−T213A−H249R、N018R−S024R−N076D−N116A−A150T−T213A−H249R、N018R−S024R−N076D−N183D−T213A−H249R、N018R−G020R−S024R−N076
D−N116A−N183D−G211Q−A215F−H249R、N018R−G020R−S024R−N076D−G211Q−H249R、N018R−S024R−N076D−S101A−N116A−N183D−I198L−H249R、S024R−N076D−A232V−H249R、N018R−G020R−T022W−S024R−N076D−S101A−N116A−N183D−I198L−G211Q−T213A−H249R、N018R−T022W−S024R−N076D−S101A−N116T−I198L−A215F−H249R、N018R−S024R−N076D−N183D−I198L−G211Q−A215F−H249R、N018R−T022R−S024R−N076D−S101A−N116A−N183D−G211Q−H249R、R045T−S101G−S103A−V104I−A232V−Q245R、N018R−G020R−S024R−N076D−S101A−N183D−G211Q−H249R、G020R−S101G−S103A−V104I−N116A−N183D−T213A−A232V−Q245R、N076D−S101G−S103A−Q245R、G020R−N043D−S078R−S101G−S103A−V104I−A232V−Q245R−H249R、N018R−S024R−N076D−N116A−N183D−H249R、N018R−S024R−N076D−S101A−N183D−G211Q−T213A−A215F−H249R、N018R−G020R−T022W−S024R−N076D−S101A−N116A−I198L−H249R、N018R−T22W−S024R−N076D−G211Q−T213A−H249R、N018R−G020R−S024R−N076D−N183D−G211Q−H249R、N018R−G020R−S024R−N076D−S101A−N116A−N183D−T213A−H249R、N043R−S078R−S101G−S103A−V104I−L217E−A232V−Q245R、N018R−T022W−S024R−N076D−S101A−A215F−H249R、N018R−G020R−S024R−N076D−S101A−N183D−I198L−G211Q−T213A−H249R、N076D−S101G−V104I−H249R、N018R−T022W−S024R−N076D−S101A−N116A−N183D−T213A−H249R、N018R−S024R−N076D−N183D−H249R、N018R−S024R−N076D−S101A−N183D−I198L−A215F−H249R、N018R−T022W−S024R−N076D−N183D−I198L−A215F−H249R、N018R−T022W−S024R−N076D−S101A−I198L−G211Q−H249R、G020R−S101A−S103A−V104I−N116A−N183D−A232V−Q245R、N018R−S024R−N076D−N116A−N183D−I198L−G211Q−H249R、N018R−G020R−S024R−S101G−S103A−V104I−A232V−Q245R、N018R−N076D−S078R−S101G−S103A−V104I−L217E−A232V−Q245R、G020R−S101A−S103A−V104I−N116A−N183D−G211Q−A232V−Q245R、N018R−T022W−S024R−N076D−S101A−N183D−I198L−Y209H−H249R、N018R−S024R−N076D−N183D−I198L−T213A−A215F−H249R、N018R−S024R−N076D−S101A−N116A−N183D−G211Q−T213A−H249R、N018R−T022W−S024R−N076D−S101A−N116A−N183D−G211Q−T213A−H249R、N018R−S024R−N076D−N183D−I198L−H249R、N018R−S024R−N076D−N183D−A215F−H249R、N018R−G020R−S024R−N076D−G211Q−T213A−A215F−H249R、N076D−Q245R、N076D−S101G−V104I−Q245R、N018R−T022W−S024R−N076D−S101A−G211Q−A215F−H249R、N018R−T022W−S024R−N076D−S101A−N116A−N183D−G211Q−A215F−H249R、N018R−G020R−T022W−S024R−N076D−S101A−G211Q−T213A−H249R、G020R−S024R−N043R−S101G−S103A−V104I−A232V−Q245R、N018R−S024R−N076D−N116A−N183D−G211Q−A215F−H249R、G020R−S101A−S103A−V104I−N116A−N183D−T213A−A215F−A232V−Q245R、S101G−S103A−V104I、N018R−G020R−S024R−N076D−S101A−N116A−N183D−G211Q−T213A−H249R、N018R−G020R−S024R−N076D−N204D−T213A−H249R、N018R−T022W−S024R−N076D−N183D−I198L−H249R、N018R−S024R−N076D−S101A−N116A−N183D−A215F−H249R、N018R−T022W−S024R−N076D−N116A−N183D−I198L−G211Q−T213A−A209V−H249R、N018R−T022W−S024R−N076D−S101A−N116A−N183D−G211Q−T213A−A215F−H249R、N018R−S024R−N076D−S101A−N116A−I198L−T213A−H249R、N018R−G020R−S024R−N076D−S101A−N116A−G211Q−T213A−H249R、N018R−G020R−T022W−S024R−N076D−S101A−N116A−N183D−G211Q−T213A−A215F−H249R、N018R−S024R−N076D−S101A−N116A−N183D−T213A−A215F−H249R、N018R−S024R−N076D−S101A−N183D−I198L−G211Q−T213A−A215F−H249R、N018R−S024R−N076D−S101A−N183D−I198L−G211Q−T213A−H249R、N018R−N043R−R045T−S078R−S101G−S103A−V104I−L217E−A232V−Q245R、N018R−S024R−N076D−N183D−G211Q−T213A−A215F−H249R、N018R−T022W−S024R−N076D−N116A−N183D−I198L−A215F−H249R、N018R−G020R−S024R−N076D−N116A−H249R、N018R−G020R−T022W−S024R−N076D−S101A−G211Q−A215F−H249R、N018R−G020R−S024R−N076D−N183D−G211Q−T213A−A215F−H249R、N018R−G020R−T022W−S024R−N076D−I198L−T213A−H249R、N018R−G020R−S024R−N076D−S101A−G211Q−A215F−H249R−N269D、N018R−G020R−N043D−S101G−S103A−V104I−A232V−Q245R−N269R、N018R−T022W−S024R−N076D−S101A−N183D−I198L−T213A−H249R、G020R−T022W−S101G−S103A−V104I−N183D−A215F−A232V−Q245R、N018R−T022W−S024R−N076D−N116A−N183D−I198L−Y209H−G211Q−H249R、N018R−G020R−T022W−S024R−N076D−S101A−N116A−N183D−G211Q−H249R、N076D−A232V−Q245R、N043D−R045T−S078R−S101G−S103A−V104I−A232V−Q245R、N018R−G020R−S024R−N076D−N116A−I198L−G211Q−A215F−Q245R、N018R−G020R−T022W−S024R−N076D−T213A−H249R、G020R−S024R−N043D−S078R−S101G−S103A−V104I−A232V−Q245R−H249R、N018R−G020R−T022W−S024R−N076D−S101A−I198L−A215F−H249R、G020R−A090S−S101G−S103A−V104I−N116A−N183D−T213A−A215F−A232V−Q245R、N018R−G020R−T022W−S024R−N076D−S101A−I198L−G211Q−T213A−A215F−H249R、N018R−G020R−S024R−N076D−S101A−N183D−T213A−A215F−H249R、N018R−S024R−N076D−N116A−N183D−I198L−G211Q−T213A−H249R、N043D−R045T−S078R−S101G−S103A−V104I−A232V−Q245R−N269R、N018R−S024R−N076D−S101A−N183D−A215F−H249R、N018R−G020R−S024R−N076D−S101A−N183D−I198L−T213A−H249R、G020R−T022W−S101A−S103A−V104I−N116A−N183D−I198L−G211Q−T213A−A215F−A232V−Q245R、N018R−G020R−S024R−N043D−N076D−S101G−S103A−V104I−A232V−Q245R−N269R、N018R−S024R−N076D−S101A−N183D−T213A−A215F−H249R、N018R−G020R−T022W−S024R−N076D−S101A−N116A−I198L−G211Q−T213A−A215F−H249R、N018R−G020R−N043D−S101G−S103A−V104I−L217E−A232V−Q245R、N076D−S103A−V104I−A232V−Q245R、R045T−N076D−S078R−S101G−S103A−V104I−A232V−Q245R−H249R、N018R−T022W−S024R−N076D−S101A−N183D−G211Q−A215F−H249R、N018R−T022W−S024R−N076D−S101A−N116A−N183D−H249R、N018R−S024R−N076D−N116A−N183D−I198L−G211Q−A215F−H249R、N018R−G020R−N043D−N076D−S078R−S101G−S103A−V104I−L217E−A232V−Q245R、N076D−S103A−V104I−Q245R、N018R−G020R−S024R−N076D−S101A−N116A−G211Q−T213A−A215F−H249R、N018R−S024R−N076D−S101A−N183D−I198L−H249R、N018R−T022W−S024R−N076D−N116A−N183D−I198L−G211Q−A215F−H249R、N018R−S024R−N076D−N116A−N183D−T213A−A215F−H249R、N018R−T022W−S0
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。
32V−X245R−X248D−X249R、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、核酸を提供する。
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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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N116A−N183D−G211Q−A215F−H249R、N018R−G020R−S024R−N076D−G211Q−H249R、N018R−S024R−N076D−S101A−N116A−N183D−I198L−H249R、S024R−N076D−A232V−H249R、N018R−G020R−T022W−S024R−N076D−S101A−N116A−N183D−I198L−G211Q−T213A−H249R、N018R−T022W−S024R−N076D−S101A−N116T−I198L−A215F−H249R、N018R−S024R−N076D−N183D−I198L−G211Q−A215F−H249R、N018R−T022R−S024R−N076D−S101A−N116A−N183D−G211Q−H249R、R045T−S101G−S103A−V104I−A232V−Q245R、N018R−G020R−S024R−N076D−S101A−N183D−G211Q−H249R、G020R−S101G−S103A−V104I−N116A−N183D−T213A−A232V−Q245R、N076D−S101G−S103A−Q245R、G020R−N043D−S078R−S101G−S103A−V104I−A232V−Q245R−H249R、N018R−S024R−N076D−N116A−N183D−H249R、N018R−S024R−N076D−S101A−N183D−G211Q−T213A−A215F−H249R、N018R−G020R−T022W−S024R−N076D−S101A−N116A−I198L−H249R、N018R−T22W−S024R−N076D−G211Q−T213A−H249R、N018R−G020R−S024R−N076D−N183D−G211Q−H249R、N018R−G020R−S024R−N076D−S101A−N116A−N183D−T213A−H249R、N043R−S078R−S101G−S103A−V104I−L217E−A232V−Q245R、N018R−T022W−S024R−N076D−S101A−A215F−H249R、N018R−G020R−S024R−N076D−S101A−N183D−I198L−G211Q−T213A−H249R、N076D−S101G−V104I−H249R、N018R−T022W−S024R−N076D−S101A−N116A−N183D−T213A−H249R、N018R−S024R−N076D−N183D−H249R、N018R−S024R−N076D−S101A−N183D−I198L−A215F−H249R、N018R−T022W−S024R−N076D−N183D−I198L−A215F−H249R、N018R−T022W−S024R−N076D−S101A−I198L−G211Q−H249R、G020R−S101A−S103A−V104I−N116A−N183D−A232V−Q245R、N018R−S024R−N076D−N116A−N183D−I198L−G211Q−H249R、N018R−G020R−S024R−S101G−S103A−V104I−A232V−Q245R、N018R−N076D−S078R−S101G−S103A−V104I−L217E−A232V−Q245R、G020R−S101A−S103A−V104I−N116A−N183D−G211Q−A232V−Q245R、N018R−T022W−S024R−N076D−S101A−N183D−I198L−Y209H−H249R、N018R−S024R−N076D−N183D−I198L−T213A−A215F−H249R、N018R−S024R−N076D−S101A−N116A−N183D−G211Q−T213A−H249R、N018R−T022W−S024R−N076D−S101A−N116A−N183D−G211Q−T213A−H249R、N018R−S024R−N076D−N183D−I198L−H249R、N018R−S024R−N076D−N183D−A215F−H249R、N018R−G020R−S024R−N076D−G211Q−T213A−A215F−H249R、N076D−Q245R、N076D−S101G−V104I−Q245R、N018R−T022W−S024R−N076D−S101A−G211Q−A215F−H249R、N018R−T022W−S024R−N076D−S101A−N116A−N183D−G211Q−A215F−H249R、N018R−G020R−T022W−S024R−N076D−S101A−G211Q−T213A−H249R、G020R−S024R−N043R−S101G−S103A−V104I−A232V−Q245R、N018R−S024R−N076D−N116A−N183D−G211Q−A215F−H249R、G020R−S101A−S103A−V104I−N116A−N183D−T213A−A215F−A232V−Q245R、S101G−S103A−V104I、N018R−G020R−S024R−N076D−S101A−N116A−N183D−G211Q−T213A−H249R、N018R−G020R−S024R−N076D−N204D−T213A−H249R、N018R−T022W−S024R−N076D−N183D−I198L−H249R、N018R−S024R−N076D−S101A−N116A−N183D−A215F−H249R、N018R−T022W−S024R−N076D−N116A−N183D−I198L−G211Q−T213A−A209V−H249R、N018R−T022W−S024R−N076D−S101A−N116A−N183D−G211Q−T213A−A215F−H249R、N018R−S024R−N076D−S101A−N116A−I198L−T213A−H249R、N018R−G020R−S024R−N076D−S101A−N116A−G211Q−T213A−H249R、N018R−G020R−T022W−S024R−N076D−S101A−N116A−N183D−G211Q−T213A−A215F−H249R、N018R−S024R−N076D−S101A−N116A−N183D−T213A−A215F−H249R、N018R−S024R−N076D−S101A−N183D−I198L−G211Q−T213A−A215F−H249R、N018R−S024R−N076D−S101A−N183D−I198L−G211Q−T213A−H249R、N018R−N043R−R045T−S078R−S101G−S103A−V104I−L217E−A232V−Q245R、N018R−S024R−N076D−N183D−G211Q−T213A−A215F−H249R、N018R−T022W−S024R−N076D−N116A−N183D−I198L−A215F−H249R、N018R−G020R−S024R−N076D−N116A−H249R、N018R−G020R−T022W−S024R−N076D−S101A−G211Q−A215F−H249R、N018R−G020R−S024R−N076D−N183D−G211Q−T213A−A215F−H249R、N018R−G020R−T022W−S024R−N076D−I198L−T213A−H249R、N018R−G020R−S024R−N076D−S101A−G211Q−A215F−H249R−N269D、N018R−G020R−N043D−S101G−S103A−V104I−A232V−Q245R−N269R、N018R−T022W−S024R−N076D−S101A−N183D−I198L−T213A−H249R、G020R−T022W−S101G−S103A−V104I−N183D−A215F−A232V−Q245R、N018R−T022W−S024R−N076D−N116A−N183D−I198L−Y209H−G211Q−H249R、N018R−G020R−T022W−S024R−N076D−S101A−N116A−N183D−G211Q−H249R、N076D−A232V−Q245R、N043D−R045T−S078R−S101G−S103A−V104I−A232V−Q245R、N018R−G020R−S024R−N076D−N116A−I198L−G211Q−A215F−Q245R、N018R−G020R−T022W−S024R−N076D−T213A−H249R、G020R−S024R−N043D−S078R−S101G−S103A−V104I−A232V−Q245R−H249R、N018R−G020R−T022W−S024R−N076D−S101A−I198L−A215F−H249R、G020R−A090S−S101G−S103A−V104I−N116A−N183D−T213A−A215F−A232V−Q245R、N018R−G020R−T022W−S024R−N076D−S101A−I198L−G211Q−T213A−A215F−H249R、N018R−G020R−S024R−N076D−S101A−N183D−T213A−A215F−H249R、N018R−S024R−N076D−N116A−N183D−I198L−G211Q−T213A−H249R、N043D−R045T−S078R−S101G−S103A−V104I−A232V−Q245R−N269R、N018R−S024R−N076D−S101A−N183D−A215F−H249R、N018R−G020R−S024R−N076D−S101A−N183D−I198L−T213A−H249R、G020R−T022W−S101A−S103A−V104I−N116A−N183D−I198L−G211Q−T213A−A215F−A232V−Q245R、N018R−G020R−S024R−N043D−N076D−S101G−S103A−V104I−A232V−Q245R−N269R、N018R−S024R−N076D−S101A−N183D−T213A−A215F−H249R、N018R−G020R−T022W−S024R−N076D−S101A−N116A−I198L−G211Q−T213A−A215F−H249R、N018R−G020R−N043D−S101G−S103A−V104I−L217E−A232V−Q245R、N076D−S103A−V104I−A232V−Q245R、R045T−N076D−S078R−S101G−S103A−V104I−A232V−Q245R−H249R、N018R−T022W−S024R−N076D−S101A−N183D−G211Q−A215F−H249R、N018R−T022W−S024R−N076D−S101A−N116A−N183D−H249R、N018R−S024R−N076D−N116A−N183D−I198L−G211Q−A215F−H249R、N018R−G020R−N043D−N076D−S078R−S101G−S103A−V104I−L217E−A232V−Q245R、N076D−S103A−V104I−Q245R、N018R−G020R−S024R−N076D−S101A−N116A−G211Q−T213A−A215F−H249R、N018R−S024R−N076D−S101A−N183D−I198L−H249R、N018R−T022W−S024R−N076D−N116A−N183D−I198L−G211Q−A215F−H249R、N018R−S024R−N076D−N116A−N183D−T213A−A215F−H249R、N018R−T022W−S024
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
1A−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
−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−G020R−T022W−S024R−N076D−S101A−G211Q−T213A−A215F−H249R、A016T−N043R−R045T−N076D−S101G−S103A−V104I−A232V−Q245R−N269R、N018R−T
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−N116A−N183D−T213A−H249R、N018R−S024R−N076D−N116A−A150T−T213A−H249R、N018R−S024R−N076D−N183D−T213A−H249R、N018R−G020R−S024R−N076
D−N116A−N183D−G211Q−A215F−H249R、N018R−G020R−S024R−N076D−G211Q−H249R、N018R−S024R−N076D−S101A−N116A−N183D−I198L−H249R、S024R−N076D−A232V−H249R、N018R−G020R−T022W−S024R−N076D−S101A−N116A−N183D−I198L−G211Q−T213A−H249R、N018R−T022W−S024R−N076D−S101A−N116T−I198L−A215F−H249R、N018R−S024R−N076D−N183D−I198L−G211Q−A215F−H249R、N018R−T022R−S024R−N076D−S101A−N116A−N183D−G211Q−H249R、R045T−S101G−S103A−V104I−A232V−Q245R、N018R−G020R−S024R−N076D−S101A−N183D−G211Q−H249R、G020R−S101G−S103A−V104I−N116A−N183D−T213A−A232V−Q245R、N076D−S101G−S103A−Q245R、G020R−N043D−S078R−S101G−S103A−V104I−A232V−Q245R−H249R、N018R−S024R−N076D−N116A−N183D−H249R、N018R−S024R−N076D−S101A−N183D−G211Q−T213A−A215F−H249R、N018R−G020R−T022W−S024R−N076D−S101A−N116A−I198L−H249R、N018R−T22W−S024R−N076D−G211Q−T213A−H249R、N018R−G020R−S024R−N076D−N183D−G211Q−H249R、N018R−G020R−S024R−N076D−S101A−N116A−N183D−T213A−H249R、N043R−S078R−S101G−S103A−V104I−L217E−A232V−Q245R、N018R−T022W−S024R−N076D−S101A−A215F−H249R、N018R−G020R−S024R−N076D−S101A−N183D−I198L−G211Q−T213A−H249R、N076D−S101G−V104I−H249R、N018R−T022W−S024R−N076D−S101A−N116A−N183D−T213A−H249R、N018R−S024R−N076D−N183D−H249R、N018R−S024R−N076D−S101A−N183D−I198L−A215F−H249R、N018R−T022W−S024R−N076D−N183D−I198L−A215F−H249R、N018R−T022W−S024R−N076D−S101A−I198L−G211Q−H249R、G020R−S101A−S103A−V104I−N116A−N183D−A232V−Q245R、N018R−S024R−N076D−N116A−N183D−I198L−G211Q−H249R、N018R−G020R−S024R−S101G−S103A−V104I−A232V−Q245R、N018R−N076D−S078R−S101G−S103A−V104I−L217E−A232V−Q245R、G020R−S101A−S103A−V104I−N116A−N183D−G211Q−A232V−Q245R、N018R−T022W−S024R−N076D−S101A−N183D−I198L−Y209H−H249R、N018R−S024R−N076D−N183D−I198L−T213A−A215F−H249R、N018R−S024R−N076D−S101A−N116A−N183D−G211Q−T213A−H249R、N018R−T022W−S024R−N076D−S101A−N116A−N183D−G211Q−T213A−H249R、N018R−S024R−N076D−N183D−I198L−H249R、N018R−S024R−N076D−N183D−A215F−H249R、N018R−G020R−S024R−N076D−G211Q−T213A−A215F−H249R、N076D−Q245R、N076D−S101G−V104I−Q245R、N018R−T022W−S024R−N076D−S101A−G211Q−A215F−H249R、N018R−T022W−S024R−N076D−S101A−N116A−N183D−G211Q−A215F−H249R、N018R−G020R−T022W−S024R−N076D−S101A−G211Q−T213A−H249R、G020R−S024R−N043R−S101G−S103A−V104I−A232V−Q245R、N018R−S024R−N076D−N116A−N183D−G211Q−A215F−H249R、G020R−S101A−S103A−V104I−N116A−N183D−T213A−A215F−A232V−Q245R、S101G−S103A−V104I、N018R−G020R−S024R−N076D−S101A−N116A−N183D−G211Q−T213A−H249R、N018R−G020R−S024R−N076D−N204D−T213A−H249R、N018R−T022W−S024R−N076D−N183D−I198L−H249R、N018R−S024R−N076D−S101A−N116A−N183D−A215F−H249R、N018R−T022W−S024R−N076D−N116A−N183D−I198L−G211Q−T213A−A209V−H249R、N018R−T022W−S024R−N076D−S101A−N116A−N183D−G211Q−T213A−A215F−H249R、N018R−S024R−N076D−S101A−N116A−I198L−T213A−H249R、N018R−G020R−S024R−N076D−S101A−N116A−G211Q−T213A−H249R、N018R−G020R−T022W−S024R−N076D−S101A−N116A−N183D−G211Q−T213A−A215F−H249R、N018R−S024R−N076D−S101A−N116A−N183D−T213A−A215F−H249R、N018R−S024R−N076D−S101A−N183D−I198L−G211Q−T213A−A215F−H249R、N018R−S024R−N076D−S101A−N183D−I198L−G211Q−T213A−H249R、N018R−N043R−R045T−S078R−S101G−S103A−V104I−L217E−A232V−Q245R、N018R−S024R−N076D−N183D−G211Q−T213A−A215F−H249R、N018R−T022W−S024R−N076D−N116A−N183D−I198L−A215F−H249R、N018R−G020R−S024R−N076D−N116A−H249R、N018R−G020R−T022W−S024R−N076D−S101A−G211Q−A215F−H249R、N018R−G020R−S024R−N076D−N183D−G211Q−T213A−A215F−H249R、N018R−G020R−T022W−S024R−N076D−I198L−T213A−H249R、N018R−G020R−S024R−N076D−S101A−G211Q−A215F−H249R−N269D、N018R−G020R−N043D−S101G−S103A−V104I−A232V−Q245R−N269R、N018R−T022W−S024R−N076D−S101A−N183D−I198L−T213A−H249R、G020R−T022W−S101G−S103A−V104I−N183D−A215F−A232V−Q245R、N018R−T022W−S024R−N076D−N116A−N183D−I198L−Y209H−G211Q−H249R、N018R−G020R−T022W−S024R−N076D−S101A−N116A−N183D−G211Q−H249R、N076D−A232V−Q245R、N043D−R045T−S078R−S101G−S103A−V104I−A232V−Q245R、N018R−G020R−S024R−N076D−N116A−I198L−G211Q−A215F−Q245R、N018R−G020R−T022W−S024R−N076D−T213A−H249R、G020R−S024R−N043D−S078R−S101G−S103A−V104I−A232V−Q245R−H249R、N018R−G020R−T022W−S024R−N076D−S101A−I198L−A215F−H249R、G020R−A090S−S101G−S103A−V104I−N116A−N183D−T213A−A215F−A232V−Q245R、N018R−G020R−T022W−S024R−N076D−S101A−I198L−G211Q−T213A−A215F−H249R、N018R−G020R−S024R−N076D−S101A−N183D−T213A−A215F−H249R、N018R−S024R−N076D−N116A−N183D−I198L−G211Q−T213A−H249R、N043D−R045T−S078R−S101G−S103A−V104I−A232V−Q245R−N269R、N018R−S024R−N076D−S101A−N183D−A215F−H249R、N018R−G020R−S024R−N076D−S101A−N183D−I198L−T213A−H249R、G020R−T022W−S101A−S103A−V104I−N116A−N183D−I198L−G211Q−T213A−A215F−A232V−Q245R、N018R−G020R−S024R−N043D−N076D−S101G−S103A−V104I−A232V−Q245R−N269R、N018R−S024R−N076D−S101A−N183D−T213A−A215F−H249R、N018R−G020R−T022W−S024R−N076D−S101A−N116A−I198L−G211Q−T213A−A215F−H249R、N018R−G020R−N043D−S101G−S103A−V104I−L217E−A232V−Q245R、N076D−S103A−V104I−A232V−Q245R、R045T−N076D−S078R−S101G−S103A−V104I−A232V−Q245R−H249R、N018R−T022W−S024R−N076D−S101A−N183D−G211Q−A215F−H249R、N018R−T022W−S024R−N076D−S101A−N116A−N183D−H249R、N018R−S024R−N076D−N116A−N183D−I198L−G211Q−A215F−H249R、N018R−G020R−N043D−N076D−S078R−S101G−S103A−V104I−L217E−A232V−Q245R、N076D−S103A−V104I−Q245R、N018R−G020R−S024R−N076D−S101A−N116A−G211Q−T213A−A215F−H249R、N018R−S024R−N076D−S101A−N183D−I198L−H249R、N018R−T022W−S024R−N076D−N116A−N183D−I198L−G211Q−A215F−H249R、N018R−S024R−N076D−N116A−N183D−T213A−A215F−H249R、N018R−T022W−S0
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 (9)
- 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S188D-E271Fの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、
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、及び
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る、
サブチリシン変異体。 - 請求項1に記載の単離されたサブチリシン変異体であって、
前記変異体が、A16S, T22A, S24R, N62E, N76D, E89P, S101A/G, S103G/A, V104L/I, L111V, S128N, P129E, A232V, L148I, A158E, G159D/E, R186H, Y209E, Q236H, Q245R, N248D/R, H249R, N252K/R, 及び T253Rから選択されるアミノ酸置換の組み合わせを更に含むアミノ酸配列からなり、及び
前記サブチリシン変異体のアミノ酸位置が、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。 - 請求項1に記載の単離されたサブチリシン変異体であって、
前記変異体が、A1R, Q2A, Q2M, Q2R, Q2S, Q2W, S3R, V4C, V4R, V4S, I8A, S9A, S9F, S9W, R10A, R10H, R10M, R10S, Q12F, Q12R, P14F, P14K, P14Q, A15F, A15R, A16S, H17F, H17M, H17R, N18K, N18R, G20F, G20K, G20R, T22A, T22L, T22Q, T22R, T22V, T22W, T22Y, G23A, G23F, G23S, S24F, S24H, S24L, S24Q, S24R, S24W, G25F, G25R, G25V, V26F, K27F, K27L, K27R, K27V, V28A, V28E, V28N, A29T, V30E, L31F, T33D, T33G, T33S, G34P, I35M, S36F, S36R, S36T, T38F, T38L, T38R, P40H, P40L, P40N, P40R, P40T, P40W, L42I, N43A, N43D, N43F, N43I, N43M, N43R, N43S, N43W, R45T, G46R, A48R, F50C, V51F, V51H, V51W, P52E, P52F, P52N, P55Y, T57R, Q59A, Q59F, Q59R, D60A, D60P, D60Q, N62E, N62Q, G63A, G63D, G63E, G63H, G63I, G63M, G63P, G63Q, G63S, G63T, G63V, H64F, H64T, V68A, V68C, A69N, A69P, A69T, A69W, T71G, I72C, A74C, L75A, L75E, L75F, L75R, N76D, S78I, S78N, S78R, I79Q, I79W, V81R, L82F, L82M, L82R, L82T, L82V, A85M, P86I, P86L, P86W, E89F, E89G, E89H, E89I, E89L, E89P, E89T, E89V, E89W, Y91F, Y91N, A92F, K94N, S99F, S99G, S99M, S99P, S99T, G100I, G100N, G100Q, G100S, S101A, S101D, S101E, S101F, S101G, S101N, S101P, S101T, G102A, G102E, G102H, G102N, G102T, S103A, S103D, S103G, S103N, V104D, V104E, V104I, V104L, S105E, S105Q, S105T, S106A, S106D, S106E, S106F, S106G, S106T, S106V, I107F, I107M, A108G, A108I, Q109M, L111I, L111V, E112L, E112Q, E112V, A114G, G115K, G115R, N116A, N116K, N116L, N117F, G118I, G118R, M119C, H120A, H120F, H120R, V121E, V121F, N123E, N123G, L124S, S128D, S128F, S128H, S128I, S128L, S128M, S128N, S128Q, P129E, S132A, S132E, A138G, S144R, V147L, L148I, A158E, G159C, G159D, G159E, S160D, S166D, S166E, Y167W, M175V, V177C, D181A, Q182R, N183D, N183F, N183I, N183M, N183R, N185E, N185I, N185V, R186H, R186K, Y192H, Y192W, A194E, A194F, A194V, D197F, I198F, I198L, V203C, V203E, T208S, Y209E, Y209F, Y209G, Y209H, Y209L, Y209N, Y209S, Y209T, P210L, P210R, P210V, G211Q, G211R, S212F, S212I, S212M, T213A, Y214F, A215D, A215E, A215F, A215H, A215N, S216A, S216F, L217D, L217E, L217N, N218D, N218E, N218P, T224A, T224G, V227I, A230E, A231C, A231I, A232V, L233C, V234F, K235F, Q236F, Q236H, Q236N, N238K, N238L, N238R, P239F, P239G, P239H, P239K, P239N, P239R, P239S, P239T, S240R, W241R, S242L, S242R, N243F, N243R, V244R, Q245R, I246S, N248D, N248I, N248R, N248V, H249R, H249T, L250I, K251R, K251S, N252F, N252H, N252I, N252K, N252R, T253F, T253I, T253R, A254C, S256N, G258R, T260I, T260V, L262D, L262H, Y263F, S265F, L267M, L267N, L267V, N269I, N269R, A270C, A272F, A272R, A273F, A273I, 及びT274Gから選択されるアミノ酸置換の組み合わせを更に含むアミノ酸配列からなり、及び
前記サブチリシン変異体のアミノ酸位置が、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。 - 前記プロテアーゼ変異体が、配列番号2のアミノ酸配列とは異なるアミノ酸配列からなり、かつ前記プロテアーゼ変異体の合計正味電荷が前記バチルス・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に対して0、+1、+2、+3、+4、+5、−1、−2、−3、−4、又は−5であり、
前記合計正味電荷が、N43D, R45T, N62E, N76D, S101D, P129E, A158E, G159D, G159E, S166D, S188D, A230E, N18R, G20K, G20R, T22R, S24R, N43R, G118R, Q245R, H249R, N269R, 及び E271Fから選択された1以上の置換により得られ、及び
前記プロテアーゼ変異体のアミノ酸位置が、前記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、前記バチルス・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、
請求項1〜3のいずれか一項に記載のプロテアーゼ変異体。 - 前記プロテアーゼ変異体が、次の特性:a)試験方法2による性能指数が、少なくとも1.1である;b)試験方法3による性能指数が、少なくとも1.1である;c)試験方法4による性能指数が、少なくとも1.1である;及び/あるいはd)試験方法6による性能指数が、少なくとも1.1である、のうちの1つ以上を有する、請求項1〜4のいずれか一項に記載のプロテアーゼ変異体。
- 請求項1〜5のいずれか一項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6に記載の核酸を含む、発現ベクター。
- 請求項7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1〜5のいずれか一項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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