CN1183118A - Thermitase variants having decreased adsorption and increased hydrolysis - Google Patents
Thermitase variants having decreased adsorption and increased hydrolysis Download PDFInfo
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- CN1183118A CN1183118A CN96193608A CN96193608A CN1183118A CN 1183118 A CN1183118 A CN 1183118A CN 96193608 A CN96193608 A CN 96193608A CN 96193608 A CN96193608 A CN 96193608A CN 1183118 A CN1183118 A CN 1183118A
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- 229930182478 glucoside Natural products 0.000 description 1
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- 101150008103 hal gene Proteins 0.000 description 1
- IIRDTKBZINWQAW-UHFFFAOYSA-N hexaethylene glycol Chemical compound OCCOCCOCCOCCOCCOCCO IIRDTKBZINWQAW-UHFFFAOYSA-N 0.000 description 1
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- DCPMPXBYPZGNDC-UHFFFAOYSA-N hydron;methanediimine;chloride Chemical compound Cl.N=C=N DCPMPXBYPZGNDC-UHFFFAOYSA-N 0.000 description 1
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- IZXGZAJMDLJLMF-UHFFFAOYSA-N methylaminomethanol Chemical compound CNCO IZXGZAJMDLJLMF-UHFFFAOYSA-N 0.000 description 1
- 238000003032 molecular docking Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
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- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 150000003009 phosphonic acids Chemical class 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 229910052615 phyllosilicate Inorganic materials 0.000 description 1
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- 239000011148 porous material Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical class CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 238000010926 purge Methods 0.000 description 1
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- 229940085605 saccharin sodium Drugs 0.000 description 1
- 239000003352 sequestering agent Substances 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
- DZCAZXAJPZCSCU-UHFFFAOYSA-K sodium nitrilotriacetate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CC([O-])=O DZCAZXAJPZCSCU-UHFFFAOYSA-K 0.000 description 1
- 229940067741 sodium octyl sulfate Drugs 0.000 description 1
- 229960001922 sodium perborate Drugs 0.000 description 1
- 239000004328 sodium tetraborate Substances 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- WFRKJMRGXGWHBM-UHFFFAOYSA-M sodium;octyl sulfate Chemical compound [Na+].CCCCCCCCOS([O-])(=O)=O WFRKJMRGXGWHBM-UHFFFAOYSA-M 0.000 description 1
- YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
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- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- FAGUFWYHJQFNRV-UHFFFAOYSA-N tetraethylenepentamine Chemical compound NCCNCCNCCNCCN FAGUFWYHJQFNRV-UHFFFAOYSA-N 0.000 description 1
- 150000004685 tetrahydrates Chemical class 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
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- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
- A61K8/66—Enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
-
- 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
- C11D3/0005—Other compounding ingredients characterised by their effect
- C11D3/0078—Compositions for cleaning contact lenses, spectacles or lenses
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/52—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from bacteria or Archaea
Abstract
The present invention relates to Thermitase variants having a modified amino acid sequence of wild-type Thermitase amino acid sequence, the wild-type amino acid sequence comprising a first loop region, a second loop region, a third loop region, a fourth loop region, a fifth loop region and a sixth loop region; wherein the modified amino acid sequence comprises different amino acids than that occurring in wild-type Thermitase (i.e., substitution) at specifically identified positions in one or more of the loop regions whereby the Thermitase variant has decreased adsorption to, and increased hydrolysis of, an insoluble substrate as compared to the wild-type Thermitase. The present invention also relates to DNA sequences encoding such Thermitase variants. The present invention also relates to compositions comprising such Thermitase variants for cleaning a variety of surfaces.
Description
Technical field
The present invention relates to the dna sequence dna of new enzyme variant body that is used for various cleaning composition and coding this kind of enzyme varient.
Background of invention
Enzyme has constituted the protein of the natural generation of maximum kind.The different types of chemical reaction of the common catalysis of each fermentoid (accelerated reaction and be not consumed).Being called that a kind of enzyme of proteolytic enzyme is known can hydrolysis (decomposition compound becomes two or more simpler compounds, accepts the H and the OH part of water molecules in the both sides of the chemical bond of fracture) other protein.Natural generation added this ability of promptly having utilized protein hydrolysate in the detergent for washing clothes preparation with protein engineering proteolytic enzyme as additive.Many dirts on clothes are proteinic, and the proteolytic enzyme of wide spectrum can significantly improve removing of this dirt.
Unfortunately, these protein are natural at it, and the efficacy levels in the environment of bacterium can not be transferred to non-natural relatively wash environment usually.Especially property of protease, for example thermostability, pH stability, oxidative stability and substrate characteristic may not reach best for the application outside the natural surroundings of enzyme.
The aminoacid sequence of proteolytic enzyme has determined the feature of proteolytic enzyme.According to the site that changes in the aminoacid sequence, character and/or amplitude, the characteristic that the aminoacid sequence of change proteolytic enzyme can change enzyme is to the degree that has nothing in common with each other, even deactivatable enzyme.People have made many trials changing the wild-type amino acid sequence of proteolytic enzyme, improving their character, thereby increase the efficient of proteolytic enzyme in wash environment.These trials comprise the change aminoacid sequence so that improve thermostability and improve oxidative stability under significantly different condition.
Although described various trials in the prior art, people still constantly need be used to wash the new effectively varient of the proteolytic enzyme on various surfaces.
Goal of the invention
Hot enzyme (Thermitase) varient of the hydrolytic action that the object of the present invention is to provide compares with wild-type enzyme has improvement.
Another object of the present invention is to provide the cleaning composition that contains these subtilisin variants.
Summary of the invention
The present invention relates to have the hot enzyme variant body of the modified amino acid sequence of the hot enzyme amino acid sequence of wild-type, the wild-type amino acid sequence comprises the first ring zone, the second ring zone, the 3rd ring zone, zone, Fourth Ring and zone, five rings; Wherein, contain the amino acid different (promptly replacing) on the site of the specific markers of aminoacid sequence in one or more rings zone of modifying with the hot enzyme of wild-type, compare with the hot enzyme of wild-type, hot enzyme variant body has the adsorption of not dissolving the substrate reduction and the hydrolytic action of increase.The invention still further relates to the dna sequence dna of this hot enzyme variant body of coding.The invention still further relates to the composition that is used to wash various surfaces that contains this hot enzyme variant body.
The hot enzyme variant body of detailed Description Of The Invention I.
The present invention relates to the subtilisin class, especially hot enzyme, the sudden change of their various nucleotide sequences by codase, thus change the aminoacid sequence of enzyme and modified.Modification subtilisin of the present invention (hereinafter referred to as " hot enzyme variant body ") is compared with the hot enzyme of wild-type, has not dissolving the adsorption that substrate reduces and the hydrolytic action of increase.The invention still further relates to the dna sequence dna of this hot enzyme variant body of coding.
Subtilisin of the present invention belongs to and is called protease.Proteolytic enzyme is the catalyzer of fracture peptide bond.One type proteolytic enzyme is serine protease.Serine is characterised in that and has essential serine residue on avtive spot.
Along with the increase enzyme of enzyme concn has been made abundant report to the phenomenon of the hydrolysis rate increase of solubilized substrate.Thereby, for the substrate of surface bonding, situation about in many washings are used, running into for example, hydrolysis rate increases seemingly possible along with the increase of surface concn, and this is by statement of facts.(Brode, P.F.III and D.S.Rauch, LANGMUIR, " subtilisin BPN ' " activity on the immobilization substrate ", volume 8,1325-1329 page or leaf (1992)).In fact, when the surface concn of enzyme changes, had been found that the linear relation of surface concn and speed for not dissolving substrate.(Rubingh, D.N. and M.D.Bauer. " catalytic hydrolysis of the proteolytic enzyme on the protein soln interface " polymer solution: mixed and interface (, POLYMER SOLUTIONS, BLENDSAND INTERFACES), I.Noda and D.N.Rubingh, Elsevier writes the 464th page (1992)).Unexpectedly, when attempting that this principle is used to study the varient proteolytic enzyme that obtains better scourability, we can not find to adsorb more enzyme and obtain preferable performance.In fact, we are surprised to find the fact in contrast: the substrate hydrolysis that the absorption of the decline of enzyme-to-substrate causes increasing (that is, scourability) preferably.
Although do not wish to be bound by any theory, we believe, when with varient mutually relatively the time, the performance of improvement is the result of the following fact, promptly adsorbs the also not too closely combination of less enzyme, thereby the surface of not dissolving protein substrate is easier moves desiring to remove.Under comparable enzyme solution concentration, the locomotivity of increase is enough to surpass any advantage by provide the higher concentration enzyme to give to the surface.
The sudden change that the present invention describes is used for the absorption of the dirt of change (promptly reducing) enzyme and surface bonding.In hot enzyme, some amino acid forms outer shroud on the enzyme molecule.In order to discuss, these rings can be described as first, second, third, fourth and the zone, five rings.Specifically, site 66-73 forms the first ring zone; Site 103-115 forms the second ring zone; Site 134-141 forms the 3rd ring zone; Site 162-171 forms the zone, Fourth Ring; Site 191-195 forms the zone, five rings; Form the 6th ring zone (the site numbering is similar to the aminoacid sequence of the hot enzyme of wild-type subtilisin (SEQ ID NO:1)) with site 204-224.
We believe that these ring zones play an important role in the absorption of the peptide of enzyme molecule and surface bonding, concrete sudden change has a significant effect to absorption in one or more rings zone.Although do not wish to be bound by any theory, we believe that at least two reasons these ring zones are important to the absorption of hot enzyme molecule.At first, containing the regional amino acid of ring can contact with any surface that molecule exposes nearly.Secondly, the ring of hot enzyme molecule zone and avtive spot near and combine capsule and make them in the absorption of the catalysis generation of the substrate (peptide/protein dirt) of enzyme and surface bonding, work.
Term used herein " varient " is meant and contains the enzyme that is different from the wild-type amino acid sequence.
Term used herein " hot enzyme dna suddenlys change " refers to the dna sequence dna of the hot enzyme variant body of coding.
Term used herein " the hot enzyme of wild-type " refers to the enzyme of being represented by SEQ ID NO:1.The aminoacid sequence of this hot enzyme is at Meloun, B., and Baudys, M, Kostka, V., Hausdorf, G, Frommel, C., and Hohne, W.E., FEBA LETT. further describes in volume 183, the 195-200 pages or leaves (classifying reference as).
Term used herein " hot enzyme wild-type amino acid sequence " comprises SEQ ID NO:1 and removes site 66,67,68,69,70,72,73,103,104,105,106,107,108,109,110,111,112,113,114,115,134,135,136,137,138,139,140,141,162,163,164,165,166,167,168,169,170,171,191,192,193,194,195,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222, outside 223 or 224 to the SEQ ID NO:1 of amino acid sequence modifications.
Term used herein " more hydrophilic amino acid " refers to any other amino acid that has bigger hydrophilicity value with reference to the hydrophilicity value in the following table than target amino acid.Following hydrophilicity value table (table 1) with the descending order of the hydrophilicity value that increases list amino acid (referring to Hopp, T.P., and Woods.K.R., " judge the proteantigen determinant ", institute of NAS periodical, volume 78 by aminoacid sequence, the 3824-3828 page or leaf, 1981, classify reference as).
Table 1 amino acid hydrophilicity value Trp-3.4 Phe-2.5 Tyr-2.3Leu, Ile-1.8 Val-1.5 Met-1.3 Cys-1.0Ala, His-0.5 Thr-0.4Pro, Gly-0.0Gln, Asn 0.2 Ser 0.3Arg
+, Lys
+, Glu
-, Asp
-3.0
Table l has also illustrated and has had electric charge (this feature is based on the pH of about 8-9).The amino acid of positive charge is Arg and Lys, and negative charge amino acid is Glu and Asp, and remaining amino acid is neutral.In a preferred embodiment of the invention, substituted amino acid is neutral or negative charge, more preferably negative charge (being Glu or Asp).
Thereby, for example explanation " with equate more hydrophilic neutrality or have the Gln of the aminoacid replacement of negative charge " refer to Gln with Asn (it equates with the wetting ability of Gln) or Ser, Glu or Asp (they are more hydrophilic than Gln) replacement.They each all be neutral or have negative charge, compares with Gln, and they have bigger hydrophilicity value.Equally, illustrate that " with more hydrophilic neutrality or have the Pro of the aminoacid replacement of negative charge " refers to the Pro that replaces with Gln, Asn, Ser, Glu or Asp.
In one embodiment of the invention, hot enzyme variant body has the modified amino acid sequence of hot enzyme wild-type amino acid sequence, and wherein the wild-type amino acid sequence contains the substituting group on one or more sites in regional one or more of the first ring zone, the second ring zone, the 3rd ring zone, zone, Fourth Ring, zone, five rings or the 6th ring; Thereby hot enzyme variant body is compared with the hot enzyme of wild-type, has the hydrolytic action of the adsorption and the increase of reduction to not dissolving substrate.
In a preferred embodiment of the invention, one or more sites substituted amino acid in one or more rings zone, reference table 1, be neutral or negative charge, comparing with the amino acid of target site in the wild-type aminoacid sequence, is equal or more hydrophilic, preferably more hydrophilic.A. the replacement in the first ring zone
When replacement occurs in the first ring zone, replace and to occur on site 66,67,68,69,70,72 or 73 one or more.
When replacement occurred in site 66, substituted amino acid was Asn, Asp, Glu or Ser.
When replacement occurred in site 67, substituted amino acid was Asn, Asp, Glu or Ser.
When replacement occurred in site 68, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser.
When replacement occurred in site 69, substituted amino acid was Asp, Gln, Glu or Ser.
When replacement occurred in site 70, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser.
When replacement occurred in site 72, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser.
When replacement occurred in site 73, substituted amino acid was Asn, Asp, Gln, Glu, Gly, Pro or Ser.B. the replacement in the second ring zone
When replacement occurs in the second ring zone, replace and to occur on site 103,104,105,106,107,108,109,110,111,112,113,114 or 115 one or more.
When replacement occurred in site 103, substituted amino acid was Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Met, Pro, Ser or Thr.
When replacement occurred in site 104, substituted amino acid was Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Met, Pro, Ser, Thr or Val.
When replacement occurred in site 105, substituted amino acid was Glu.
When replacement occurred in site 106, substituted amino acid was Asp, Gln, Glu or Ser.
When replacement occurred in site 107, substituted amino acid was Asp or Glu.
When replacement occurred in site 108, substituted oxy acid was Asn, Asp, Gln, Glu, Pro or Ser.
When replacement occurred in site 109, substituted amino acid was Asp or Glu.
When replacement occurred in site 110, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser.
When replacement occurred in site 111, substituted amino acid was Asn, Asp, Gln, Glu, Gly, Pro or Ser.
When replacement occurred in site 112, substituted amino acid was Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Met, Phe, Pro, Ser, Thr, Tyr or Val.
When replacement occurred in site 113, substituted amino acid was Asn, Asp, Gln, Glu, Gly, Pro or Ser.
When replacement occurred in site 114, substituted amino acid was Asn, Asp, Gln, Glu, Gly, His, Pro, Ser or Thr.
When replacement occurred in site 115, substituted amino acid was Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Met, Pro, Ser or Thr.C. the replacement in the 3rd ring zone
When replacement occurs in the 3rd ring zone, replace to take place on site 134,135,136,137,138,139,140 or 141 one or more.Wherein
When replacement occurred in site 134, substituted amino acid was Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Met, Pro, Ser, Thr or Val.
When replacement occurred in site 135, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser.
When replacement occurred in site 136, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser.
When replacement occurred in site 137, substituted amino acid was Asn, Asp, Gln, Glu, Gly, Pro or Ser.
When replacement occurred in site 138, substituted amino acid was Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Met, Pro, Ser or Thr.
When replacement occurred in site 139, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser.
When replacement occurred in site 140, substituted amino acid was Asp, Gln, Glu or Ser.With
When replacement occurred in site 141, substituted amino acid was Asp or Glu.D. the replacement in the zone, Fourth Ring
When replacement occurs in the zone, Fourth Ring, replace and to occur on site 162,163,164,165,166,167,168,169,170 or 171 one or more.
When replacement occurred in site 162, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser.
When replacement occurred in site 163, substituted amino acid was Asp, Gln, Glu or Ser.
When replacement occurred in site 164, substituted amino acid was Asn, Asp, Gln, Glu, Gly, His, Pro, Ser or Thr.
When replacement occurred in site 165, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser.
When replacement occurred in site 166, substituted amino acid was Asp, Gln, Glu or Ser.
When replacement occurred in site 167, substituted amino acid was Asn, Asp, Gln, Glu, Gly, Pro or Ser.
When replacement occurred in site 168, substituted amino acid was Asn, Asp, Gln, Glu, Gly, His, Pro, Ser or Thr.
When replacement occurred in site 169, substituted amino acid was Asn, Asp, Gln, Glu, Gly or Ser.
When replacement occurred in site 170, substituted amino acid was Asp, Gln, Glu or Ser; With
When replacement occurred in site 171, substituted amino acid was Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Met, Pro, Ser, Thr or Val.E. the replacement in the zone, five rings
When replacement occurs in the zone, five rings, replace occur in site 191,192,193,194 or 195 one or more on.
When replacement occurred in site 191, substituted amino acid was Asp or Glu.
When replacement occurred in site 192, substituted amino acid was Asp or Glu.
When replacement occurred in site 193, substituted amino acid was Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Met, Pro, Ser, Thr, Tyr or Val.
When replacement occurred in site 194, substituted amino acid was Asp or Glu.
When replacement occurred in site 195, substituted amino acid was Asn, Asp, Gln, Glu, Gly, Pro or Ser.Replacement in F the 6th ring zone
When replacement occurs in the 6th ring zone, replace and to occur on site 204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222,223 or 224 one or more.
When replacement occurred in site 204, substituted amino acid was Asn, Asp, Gln, Glu, Gly, His, Pro, Ser or Thr.
When replacement occurred in site 205, substituted amino acid was Asn, Asp, Gln, Glu, Gly or Ser.
When replacement occurred in site 206, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser.
When replacement occurred in site 207, substituted amino acid was Asp or Glu.
When replacement occurred in site 208, substituted amino acid was Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Met, Phe, Pro, Ser, Thr, Tyr or Val.
When replacement occurred in site 209, substituted amino acid was Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Leu, Met, Pro, Ser, Thr or Val.
When replacement occurred in site 210, substituted amino acid was Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Met, Pro, Ser, Thr or Val.
When replacement occurred in site 211, substituted amino acid was Asp or Glu.
When replacement occurred in site 212, substituted amino acid was Asn, Asp, Gln, Glu, Gly, Pro or Ser.
When replacement occurred in site 213, substituted amino acid was Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Met, Phe, Pro, Ser, Thr or Val.
When replacement occurred in site 214, substituted amino acid was Asn, Asp, Gln, Glu, Gly or Ser.
When replacement occurred in site 215, substituted amino acid was Asn, Asp, Gln, Glu, Gly, Pro or Ser.
When replacement occurred in site 216, substituted amino acid was Asp or Glu.
When replacement occurred in site 217, substituted amino acid was Asn, Asp, Gln, Glu, Gly, Pro or Ser.
When replacement occurred in site 218, substituted amino acid was Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Met, Pro, Ser, Thr or Val.
When replacement occurred in site 219, substituted amino acid was Asn, Asp, Gln, Glu, Gly, His, Pro, Ser or Thr.
When replacement occurred in site 220, substituted amino acid was Asp or Glu.
When replacement occurred in site 221, substituted amino acid was Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Met, Pro, Ser, Thr or Val.
When replacement occurred in site 222, substituted amino acid was Asp or Glu.
When replacement occurred in site 223, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser.
When replacement occurred in site 224, substituted amino acid was Asn, Asp, Gln, Glu, Gly, Pro or Ser.G. the preparation of enzyme variant body
Embodiment 1
Sudden change body heat enzyme dna
Made up the phagemid (" TP ") that contains the hot enzyme gene of wild-type.2.8Kbp Pvu II restriction enzyme fragment (Vieira with plasmid pUC119, J. and Messing, J, " preparation of the plasmid DNA of strand ", 153 Enzymology method 3-11 (1989)) be cloned into plasmid pUB110 (Bacillus GeneticStock Center, Columbus, PvuII site OH1E9).PUC 119-pUB110 hybrid plasmid is called as pJMA601.Be cloned into the hot enzyme gene of PCR amplification with TP at the Bam of pJMA601 H1 restriction site.Phagemid TP is transformed into intestinal bacteria Ung-bacterial strain CJ236, with VCSM13 helper phage (Kunkel, T.A, J.D.Roberts and R.A.Zakour, " need not the quick and effective rite-directed mutagenesis of Phenotypic Selection ", Enzymology method, volume 154,367-382 page or leaf (1987); By Yuckenberg, P.D., F.Witney, J.Geisselsoder and J.McClary improve, and " use contains the DNA of uridylic and the external rite-directed mutagenesis of phagemid carrier ", rite-directed mutagenesis operational guidance M.J.McPherson compiles, 27-48 page or leaf (1991); All classify this paper reference as) the preparation strand contain the ura DNA template.Use single primer site-directed mutagenesis modifying method (Zoller of Zoller and Smith method, M.J. with M Smith, " the oligonucleotide directed mutagenesis of use M13 deutero-carrier: a kind of effective and common method of preparation point mutation in any fragment of DNA ", the research of nuclear ester, volume 10,6487-6500 page or leaf (1982) is classified this paper reference as) prepare all mutant (basically as people such as above-mentioned Yuckenberg, 1991 in explanation).Oligonucleotide uses the preparation of Applied Biosystem Inc.380B dna synthesizer.The jump reaction product is transferred among the coli strain MM294 (American type culture collection intestinal bacteria 33625).All mutant are confirmed by dna sequencing, separated DNA is transformed into the (Yang to subtilis expression strain BG2036, M.Y., E.Ferrari and D.J.Henner, (1984), " clone of the neutral protease gene of subtilis and cloned genes are used to produce the external deletion mutantion that obtains ", bacteriology magazine, volume 160, the 15-21 page or leaf).For some mutant, the modification TP that is used in frameshit terminated codon mutation in the respective rings prepares the uridylic template.Oligonucleotide is used for recovering suitable reading frame and is coded in site 66,67,68,69,70,72,73,103,104,105,106,107,108,109,110,111,112,113,114,115,134,135,136,137,138,139,140,141,162,163,164,165,166,167,168,169,170,171,191,192,193,194,195,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222,223 or 224 replacement at random (in these codons for all three kinds of all four kinds of oligonucleotide of base etc. the mole and/or variable mixture).Proofread and correct the ability explanation of the sudden change of frameshit termination and preparation functional enzyme by their casein digestions.Replace at random with dna sequencing and determine.
Embodiment 2
Fermentation
Bacillus subtilis mycetocyte (BG2036) being cultured in 1 liter of LB-glucose broth that to contain interested subtilis mutant contrasts mid-term, at the Biostat ED of 10 liters of cumulative volumes fermentor tank (B.Braun Biotech, Inc., Allentown, Pennsylvania) the middle cultivation.Fermention medium contains yeast extract, starch, defoamer, buffer reagent and trace minerals (referring to fermentation, operational guidance, B.McNeil and L.M.Harvey volume, 1990).In the fermentation test process, meat soup keeps constant pH 7.0.Adding paraxin selects with the microbiotic that carries out the mutagenesis plasmid.Cell is about 60 to A600 37 ℃ of grow overnight, and results.
Embodiment 3
Purify
Fermenting broth is carried out following steps to obtain pure enzyme.By the centrifugal bacillus subtilis mycetocyte of removing in the meat soup, remove thin particle and clarify by block film with 100K.Block on the film concentrating then with 10K, carry out the fluid dialysis, regulate pH to 5.5 with 0.025M MES buffer reagent (2-(N-morpholino) ethyl sulfonic acid) to reduce ionic strength.By enzyme being added cation-exchange chromatography post or affinity adsorption chromatography post, by in the post with sodium-chlor or propylene glycol gradient elution and be further purified (referring to, Scopes, R.K., protein purification theory and practice, Springer-Verlag, NewYork (1984) classifies this paper reference as).
Use pNA test (C.Largman, J.W.Brodrick and M.C.Geokas, the biological chemistry yearbook, volume 99,316-320 page or leaf (1979) is classified this paper reference as for DelMar, E.G.) to be determined at the organized enzyme concentration of the fraction of collecting in the gradient elution process.This experimental measurement is when the synthetic substrate of enzymic hydrolysis dissolved, discharges the speed of p-Nitraniline during succinyl--alanyl-alanyl-prolyl-phenyl alanyl-p-Nitraniline (sAAPF-pNA).Measure hydrolysis reaction with spectrophotometer at 410nm and produce xanchromatic speed, proportional with organized enzyme concentration.In addition, the absorption measurement at 280nm is used for measuring total protein concentration.Organized enzyme/gross protein ratio obtains the purity of enzyme, and is used to identify the fraction as the collection of storage solution.
For avoiding the self-dissolving of enzyme in storage process, in the fraction of the collection that obtains by chromatography column, add the propylene glycol of equal weight.After purification process is finished, SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis) verification of storage enzyme solution, with trypsin inhibitor type II-T: (St.Louis, Missouri) the turkey white of an egg of Gou Maiing is through the absolute enzyme concn of active sites titration measuring by Sigma Chemical Company.The transformation ratio of measuring will illustrate that the change of different loci generation in the enzyme molecule makes the enzyme variant body compare with wild-type dissolving substrate pNA is had the activity of increase.
In the preparation that uses, enzyme storage solution passes through Sephadex-G25 (Pharmacia, Piscataway, New Jersey) size exclusion post to remove propylene glycol and exchange buffering agent.With the MES buffer reagent of the 0.1M Tris buffer reagent that contains 0.01M calcium chloride (three (hydroxymethyl-amino) methane) replacement in enzyme storage solution, regulate pH to 8.6 with hydrochloric acid.Under 25 ℃ of constant temperature, in the Tris buffer reagent, under pH8.6, carry out all tests.H. the characteristic of enzyme variant body
Embodiment 4
The model surface preparation
The hole glass (CPG) of the aminopropyl control of being bought by CPG Inc. (Fairfield, New Jersey) is as covalently bound by Bachem, Inc. (Torence, California) carrier of the sAAPD-pNA substrate of Gou Maiing.Be reflected in the dimethyl sulfoxide (DMSO) and carry out, (EDC) make coupling agent with (1-ethyl-3-[3-(dimethylamino) propyl group] carbodiimide hydrochloride).After reaction is finished, (use the pNA test monitoring), remove excessive solvent, with dimethyl sulfoxide (DMSO) (DMSO) and bi-distilled water rinsing CPG:sAAPF-pNA.Nitrogen purging is dry under about 70 ℃ in baking oven then.The preparation method of reaction scheme and fixed substrate such as Brode, P.F.III, and D.S.Rauch, " subtilisin BPN ': the activity on immobilized substrate ", LANGMUIR describes in the volume 8,1325-1329 page or leaf (1992) (classifying this paper reference as) and carries out.
CPG contains on the surface 62000 ± 7000pNA molecule/μ m
250.0m from the CPG of CPG Inc. report
2The value of/g, surface-area keep not becoming.This explanation is used for not destroying pore structure (mean diameter 486A) in the method for CPG adding sAAPf-pNA.
Embodiment 5
The surface hydrolysis test
Use CPG:sAAPf-pNA, the hydrolysis of the absorption of enzyme variant body and CPG-bonded peptide can be measured in same test.In the flask of the CPG:sAAPF-pNA that contains the Tris buffer reagent and outgased, add a spot of enzyme variant body storage solution.Flask vibrated 90 minutes in the vibrator of piston action, during this period, with different timed interval failure of oscillations devices (for example, in the initial period of adsorption of hydrolyzation effect, for example initial 20 minutes for per 2 minutes-when experiment finishes, be per 10 minutes).CPG:sAAPF-pNA is left standstill, sampling solution.As people such as above-mentioned Brode, adsorb experimentation and calculating described in 1991 with hydrolysis.
Measure the self-dissolving stability of all enzymes, in the time of experiment, should not show tangible self-dissolving loss.Therefore, enzyme absorption can be measured by measuring solution consumption.The amount of the enzyme variant body that initial enzyme variant bulk concentration and the difference between the concentration of each interlude point measurement obtain adsorbing.Measure by the absorption reading of sample when the 410nm by the amount of the pNA of surface hydrolysis.The total amount of the pNA of hydrolysis adds the amount calculating that remains in the flask by the amount of sampling.This value is calibrated by deducting when not having enzyme under pH8.6 by the amount of the pNA of Tris buffer reagent hydrolysis.According to the efficient of enzyme, benchmark hydrolysis scope is the 7-29% of total hydrolysis.
Embodiment 6
The dynamic analysis of solubilized substrate
The hydrolysis rate of solubilized substrate sAAPF-pNA is monitored by measuring as the absorption increment of the function of time under 410nm with the DU-70 spectrophotometer.It is constant that enzyme concn keeps, and be prepared into the scope of 6-10 nmole, and for each kinetic determination, concentration of substrate changes between 90-700 μ MsAAPF-pNA.In 900 seconds time, per second is collected the adsorption number strong point, and data transfer is to LOTUSTM recording paper (Lotus Development Corporation, Cambridge, Massachu setts).Carry out the analysis of kinetic parameter with standard Linewweaver Burk analytical method, wherein in the data fit of test initial (being generally first few minutes) in the linear regression curve to obtain v
OThe v that marks and draws in standard mode reciprocal
OAnd s
OData obtain K
MAnd K
CatThe example of I. hot enzyme variant body
The hot enzyme variant body of the present invention of the adsorption of the substrate of reduction surface bonding and the hydrolytic action of increase illustrates in as following table 2-36.In the concrete sudden change of describing, at first provide the original amino acid that occurs in the wild-type, secondly be the site numbering, the 3rd is substituted amino acid.
Table 2
Ring 1-single mutation varient
Gln66Asn
Gln66Asp
Gln66Glu
Gln66Ser
Asn67Asp
Asn67Gln
Asn67Glu
Asn67Ser
Gly68Asn
Gly68Asp
Gly68Gln
Gly68Glu
Gly68Pro
Gly68Ser
Asn69Asp
Asn69Gln
Asn69Glu
Asn69Ser
Gly70Asn
Gly70Asp
Gly70Gln
Gly70Glu
Gly70Pro
Gly70Ser
Gly72Asn
Gly72Asp
Gly72Gln
Gly72Glu
Gly72Pro
Gly72Ser
Thr73Asn
Thr73Asp
Thr73Gln
Thr73Glu
Thr73Gly
Thr73Pro
Thr73Ser
Table 3
the two sudden change of ring 1-variant Asn68Asp, +, Gly72ProGly69Asn, +, Thr73ProAsn66Glu, +, Gly69SerAsn66Glu, +, Gly67SerGly69Gln, +, Thr73ProGly67Ser, +, Gly72SerGly67Asp, +, Thr73GlyGly69Pro, +, Ser70AspGly67Pro, +, Gly69ProAsn66Glu, +, Thr73GlyGly69Gln, +, Gly72AspAsn66Gln, +, Thr73GlyAsn68Asp, +, Thr73SerAsn66Gln, +, Gly69AsnGly67Glu, +, Thr73SerGly72Glu, +, Thr73ProAsn66Glu, +, Thr73ProGly72Asp, +, Thr73GlnAsn68Ser, +, Gly69GluGly67Pro, +, Gly69SerGly67Pro, +, Gly72AspGly69Ser, +, Gly72GluSer70Asp, +, Thr73GlnGly67Ser, +, Asn68GluGly69Ser, +, Thr73SerAsn68Asp, +, Gly69SerAsn66Ser, +, Gly72AspGly69Asp, +, Gly72SerAsn68Ser, +, Thr73ProSer70Asp, +, Thr73SerSer70Glu, +, Gly72AsnGly69Asp, +, Thr73ProGly67Glu, +, Thr73GlyGly72Asp, +, Thr73SerSer70Asp, +, Thr73AsnAsn66Ser, +, Gly69GluGly72Ser, +, Thr73GlnSer70Glu, +, Thr73SerAsn66Gln, +, Gly69Ser
Table 4
ring 1-three sudden change variant Ser70Asp, +, Gly72Gln, +, Thr73GlyGly67Ser, +, Asn68Gln, +, Ser70AspAsn66Ser, +, Gly67Asn, +, Thr73GlnAsn66Gln, +, Ser70Asp, +, Gly72AsnSer70Glu, +, Gly72Gln, +, Thr73SerGly67Pro, +, Asn68Glu, +, Thr73SerAsn66Ser, +, Gly69Gln, +, Gly72GlnAsn66Ser, +, Ser70Asp, +, Thr73GlnGly67Gln, +, Gly69Asp, +, Thr73GlnGly69Pro, +, Gly72Glu, +, Thr73SerGly67Gln, +, Gly69Asn, +, Thr73AsnAsn66Ser, +, Gly69Asp, +, Thr73AsnGly69Asp, +, Gly72Ser, +, Thr73SerAsn68Asp, +, Gly72Gln, +, Thr73SerAsn66Gln, +, Asn68Ser, +, Thr73AsnAsn68Ser, +, Gly69Ser, +, Ser70AspAsn68Gln, +, Gly69Ser, +, Thr73GlnGly67Ser, +, Gly69Pro, +, Gly72GluGly67Asn, +, Gly69Ser, +, Thr73AsnGly67Gln, +, Gly72Asn, +, Thr73GlnGly67Pro, +, Asn68Gln, +, Gly69ProGly69Asn, +, Ser70Glu, +, Thr73SerAsn66Ser, +, Ser70Glu, +, Gly72AsnGly69Gln, +, Ser70Asp, +, Gly72AsnGly67Ser, +, Ser70Glu, +, Thr73GlnAsn66Glu, +, Gly67Gln, +, Thr73ProGly67Ser, +, Gly72Glu, +, Thr73SerGly67Pro, +, Gly69Gln, +, Gly72AspAsn66Ser, +, Gly67Glu, +, Thr73ProAsn66Ser, +, Gly67Glu, +, Asn68SerGly67Asn, +, Asn68Glu, +, Gly69AspAsn68Glu, +, Gly69Glu, +, Gly72ProAsn68Glu, +, Gly69Glu, +, Thr73AsnGly67Glu, +, Asn68Asp, +, Gly69GlnGly67Glu, +, Asn68Asp, +, Thr73GlnAsn66Asp, +, Gly67Asp, +, Gly72SerAsn66Glu, +, Gly67Glu, +, Thr73Pro
Table 5
ring 1-four sudden change variant Asn66Gln, +, Gly67Ser, +, Gly69Asp, +, Gly72ProAsn68Ser, +, Ser70Glu, +, Gly72Gln, +, Thr73ProAsn66Gln, +, Gly67Gln, +, Ser70Asp, +, Thr73AsnGly67Ser, +, Gly69Asp, +, Gly72Gln, +, Thr73GlyAsn66Glu, +, Gly67Ser, +, Asn68Ser, +, Thr73AsnGly67Ser, +, Asn68Asp, +, Gly72Asn, +, Thr73GlyAsn66Ser, +, Gly67Glu, +, Gly69Gln, +, Thr73GlyAsn68Glu, +, Gly69Asp, +, Gly72Asn, +, Thr73AsnGly67Glu, +, Asn68Glu, +, Gly72Asn, +, Thr73AsnAsn66Glu, +, Gly67Glu, +, Asn68Gln, +, Gly72ProAsn66Glu, +, Gly67Glu, +, Asn68Ser, +, Gly72AsnAsn66Glu, +, Gly67Glu, +, Gly72Pro, +, Thr73AsnGly67Ser, +, Gly69Asp, +, Ser70Glu, +, Thr73GlnAsn66Ser, +, Gly69Glu, +, Ser70Glu, +, Thr73GlyGly67Pro, +, Asn68Glu, +, Gly69Glu, +, Ser70GluGly67Ser, +, Asn68Glu, +, Gly69Asp, +, Ser70AspGly67Asn, +, Asn68Asp, +, Gly69Asp, +, Ser70GluGly67Asp, +, Asn68Gln, +, Gly69Glu, +, Ser70AspAsn66Gln, +, Gly67Asp, +, Gly69Asp, +, Ser70AspGly67Asp, +, Asn68Asp, +, Ser70Asp, +, Thr73AsnGly67Asp, +, Asn68Asp, +, Gly69Pro, +, Ser70GluGly67Asp, +, Asn68Gln, +, Ser70Glu, +, Gly72ProAsn66Gln, +, Gly67Glu, +, Ser70Asp, +, Gly72GlnGly67Glu, +, Ser70Glu, +, Gly72Gln, +, Thr73SerGly67Asp, +, Asn68Gln, +, Ser70Asp, +, Gly72SerGly67Glu, +, Ser70Asp, +, Gly72Ser, +, Thr73Ser
Table 6
Ring 2-single mutation varient
Val103Ala
Val103Asn
Val103Asp
Vsl103Gln
Val103Gln
Val103Glu
Val103Gly
Val103His
Val103Met
Val103Pro
Val103Ser
Val103Thr
Leu104Ala
Leu104Asn
Leu104Asp
Leu104Cys
Leu104Gln
Leu104Glu
Leu104Gly
Leu104His
Leu104Ile
Leu104Met
Leu104Pro
Leu104Ser
Leu104Thr
Leu104Val
Asp105Glu
Asn106Asp
Asn106Gln
Asn106Glu
Asn106Ser
Ser107Asp
Ser107Glu
Gly108Asn
Gly108Asp
Gly108Gln
Gly108Glu
Gly108Pro
Gly108Ser
Ser109Asp
Ser109Glu
Gly110Asn
Gly110Asp
Gly110Gln
Gly110Glu
Gly110Pro
Gly110Ser
Thr111Asn
Thr111Asp
Thr111Gln
Thr111Glu
Thr111Gly
Thr111Pro
Thr111Ser
Trp112Ala
Trp112Asn
Trp112Asp
Trp112Cys
Trp112Gln
Trp112Glu
Trp112Gly
Trp112His
Trp112Ile
Trp112Leu
Trp112Met
Trp112Phe
Trp112Pro
Trp112Ser
Trp112Thr
Trp112Tyr
Trp112Val
Thr113Asn
Thr113Asp
Thr113Gln
Thr113Glu
Thr113Gly
Thr113Pro
Thr113Ser
Ala114Asn
Ala114Asp
Ala114Gln
Ala114Glu
Ala114Gly
Ala114His
Ala114Pro
Ala114Ser
Ala114Thr
Val115Ala
Val115Asn
Val115Asp
Val115Cys
Val115Gln
Val115Glu
Val115Gly
Val115His
Val115Met
Val115Pro
Val115Ser
Val115Thr
Table 7
the two sudden change of ring 2-variant Val103Gln, +, Ser109GluAsp105Glu, +, Gly108GlnAsp105Glu, +, Gly110AsnAsp105Glu, +, Gly110ProVal103Asp, +, Thr111GlnLeu104Gln, +, Gly108AspLeu104Gly, +, Ser107GluThr111Pro, +, Ala114SerAsn106Gln, +, Ser109AspAsp105Glu, +, Gly108ProThr113Asp, +, Val115GlyVal103Met, +, Leu104GlnGly108Gln, +, Thr113AsnGly110Glu, +, Ala114GlyThr111Gln, +, Val115GlnGly110Glu, +, Thr111GlnGly108Pro, +, Ala114GluGly108Ser, +, Val115GlyAsp105Glu, +, Thr113GlnLeu104His, +, Ser107AspAsp105Glu, +, Ala114GlnGly110Gln, +, Thr113SerVal103His, +, Ala114GlnAsp105Glu, +, Trp112IleThr111Ser, +, Thr113AspLeu104His, +, Thr111GluAsn106Gln, +, Trp112TyrLeu104Gly, +, Thr113GlnVal103Thr, +, Val115AsnVal103Thr, +, Asn106SerVal103Pro, +, Thr111ProSer109Glu, +, Val115MetVal103Ala, +, Asn106GlnVal103Cys, +, Thr111GlnTrp112Gly, +, Thr113GlyVal103Gly, +, Asp105GluGly110Asn, +, Thr113GlyThr111Asn, +, Thr113GluVal103Glu, +, Trp112MetLeu104Pro, +, Ser109AspGly108Gln, +, Ala114GlyLeu104Met, +, Val115GluLeu104Gly, +, Ala114SerThr113Ser, +, Val115AlaAsp105Glu, +, Asn106GlnVal103Thr, +, Asp105GluGly110Glu, +, Val115MetVal103Gly, +, Gly110GluSer109Asp, +, Gly110GlnThr111Asp, +, Ala114SerAsn106Glu, +, Ala114ProSer109Glu, +, Thr113GlyGly108Asn, +, Trp112GluVal103Pro, +, Asn106GluAsp105Glu, +, Trp112LeuLeu104Cys, +, Asp105GluLeu104Cys, +, Thr111SerLeu104Thr, +, Ser109AspVal103Asn, +, Val115GluVal103Ser, +, Gly108Glu
Table 8
ring 2-three sudden change variant Val103Gln, +, Leu104Thr, +, Ser109GluLeu104Ser, +, Asp105Glu, +, Trp112PheAsn106Gln, +, Gly108Ser, +, Gly110GlnSer109Asp, +, Thr111Asn, +, Trp112ThrAsn106Ser, +, Gly108Gln, +, Ser109AspAsp105Glu, +, Gly108Pro, +, Val115GlyAsn106Ser, +, Ser107Asp, +, Val115GlyAsn106Ser, +, Trp112Gln, +, Val115GluLeu104Pro, +, Ser109Asp, +, Thr113GlyLeu104Asp, +, Gly110Gln, +, Val115ProGly108Asn, +, Thr111Ser, +, Ala114ProLeu104Ser, +, Asn106Ser, +, Thr111GluVal103His, +, Leu104Gln, +, Asn106AspAsn106Gln, +, Trp112Asn, +, Ala114AspVal103Met, +, Gly110Pro, +, Thr111ProLeu104Thr, +, Gly108Glu, +, Gly110AsnLeu104Ala, +, Ser109Asp, +, Trp112CysGly108Glu, +, Gly110Pro, +, Val115GlyLeu104Pro, +, Thr113Asn, +, Ala114AspVal103Asn, +, Leu104Met, +, Asn106GluVal103Cys, +, Ser109Glu, +, Val115CysVal103Gly, +, Leu104Val, +, Ser107AspGly108Pro, +, Ser109Glu, +, Trp112GlnLeu104Met, +, Trp112Cys, +, Thr113AsnAsn106Asp, +, Trp112Ile, +, Ala114SerVal103Gly, +, Ser109Glu, +, Ala114ProLeu104Ile, +, Trp112Leu, +, Thr113GlyAsn106Gln, +, Gly108Asn, +, Ser109GluVal103Asn, +, Trp112Pro, +, Ala114AspGly108Asn, +, Gly110Ser, +, Trp112GlyGly110Asp, +, Trp112Leu, +, Val115HisVal103Gly, +, Leu104Gly, +, Gly108AspLeu104Ala, +, Thr111Ser, +, Val115AlaThr111Ser, +, Thr113Asn, +, Val115HisAsp105Glu, +, Gly108Gln, +, Val115GlyLeu104Gly, +, Ala114Ser, +, Val115AlaVal103His, +, Leu104Gly, +, Asn106GluVal103Ser, +, Gly110Glu, +, Thr113ProVal103Pro, +, Gly110Asn, +, Ala114GluLeu104Met, +, Gly110Asp, +, Val115ProLeu104Asp, +, Thr111Gln, +, Trp112AlaSer109Asp, +, Gly110Pro, +, Trp112AsnLeu104Asp, +, Asp105Glu, +, Trp112CysGly108Glu, +, Ser109Glu, +, Ala114ThrGly108Asp, +, Ser109Asp, +, Thr111ProGly108Glu, +, Ser109Glu, +, Ala114AsnAsn106Ser, +, Ser109Glu, +, Gly110AspAsn106Gln, +, Ser109Asp, +, Gly110AspVal103Asp, +, Leu104Asp, +, Gly108ProLeu104Thr, +, Asp105Glu, +, Asn106GluAsp105Glu, +, Asn106Asp, +, Thr113AsnGly108Gln, +, Thr113Glu, +, Ala114GluLeu104Ser, +, Thr111Glu, +, Trp112GluAsn106Asp, +, Ser107Asp, +, Gly108AspAsp105Glu, +, Ser109Asp, +, Gly110GluTrp112Ala, +, Thr113Asp, +, Val115AspVal103Gln, +, Asp105Glu, +, Gly108AspLeu104Gln, +, Asp105Glu, +, Ser107GluSer107Asp, +, Ser109Asp, +, Thr111GlyVal103Cys, +, Ser107Asp, +, Ser109Glu
Table 9
ring 2-four sudden change variant Asp105Glu, +, Gly110Ser, +, Trp112Phe, +, Thr113SerVal103Ala, +, Ser107Asp, +, Gly110Pro, +, Ala114AsnVal103Gln, +, Gly108Pro, +, Thr111Ser, +, Ala114GluVal103Thr, +, Ser107Asp, +, Thr113Gln, +, Val115CysLeu104Asn, +, Gly110Ser, +, Thr113Glu, +, Val115GlnVal103Pro, +, Gly108Glu, +, Trp112His, +, Val115MetVal103Ala, +, Asn106Ser, +, Gly108Asp, +, Thr111AsnVal103Ala, +, Leu104Asp, +, Gly110Ser, +, Val115AlaSer109Glu, +, Trp112Pro, +, Ala114Asn, +, Val115MetVal103Thr, +, Asn106Asp, +, Gly108Ser, +, Gly110GlnVal103Pro, +, Leu104Pro, +, Asn106Ser, +, Gly110AsnSer109Glu, +, Gly110Pro, +, Thr111Ser, +, Thr113SerAsn106Gln, +, Gly108Ser, +, Trp112Tyr, +, Ala114ThrLeu104Cys, +, Gly110Gln, +, Thr111Asp, +, Thr113GlyLeu104Ser, +, Asp105Glu, +, Gly108Gln, +, Val115AsnVal103Asp, +, Gly108Asn, +, Thr113Pro, +, Ala114ProVal103Asp, +, Leu104Asn, +, Thr113Asn, +, Val115AlaVal103Asn, +, Gly110Asp, +, Thr111Asn, +, Val115CysVal103Ser, +, Asn106Glu, +, Gly110Gln, +, Val115MetLeu104Val, +, Thr111Gln, +, Trp112His, +, Ala114SerLeu104Ser, +, Asp105Glu, +, Gly110Gln, +, Thr111AsnVal103Ala, +, Asp105Glu, +, Asn106Ser, +, Gly110AsnVal103Glu, +, Gly110Ser, +, Trp112Phe, +, Val115GlyAsn106Glu, +, Thr113Asn, +, Ala114Pro, +, Val115AsnLeu104Glu, +, Asp105Glu, +, Gly108Ser, +, Gly110AsnGly108Glu, +, Ser109Glu, +, Thr111Asn, +, Ala114ProGly108Glu, +, Ser109Glu, +, Thr111Gln, +, Ala114ThrLeu104Ile, +, Gly108Pro, +, Ser109Glu, +, Gly110AspVal103Glu, +, Leu104Asp, +, Trp112Cys, +, Thr113SerAsp105Glu, +, Asn106Glu, +, Gly110Pro, +, Thr113GlyGly110Gln, +, Thr111Glu, +, Trp112Glu, +, Thr113GlySer107Asp, +, Gly108Asp, +, Ser109Asp, +, Trp112ValAsn106Asp, +, Ser107Asp, +, Gly108Glu, +, Val115ProAsp105Glu, +, Ser107Glu, +, Gly108Asp, +, Gly110SerAsp105Glu, +, Gly108Asp, +, Ser109Glu, +, Thr111GlnAsp105Glu, +, Gly108Glu, +, Ser109Glu, +, Thr111ProLeu104Asp, +, Ser109Glu, +, Trp112Asn, +, Ala114GlyVal103Ser, +, Leu104Glu, +, Gly108Asn, +, Ser109GluAsp105Glu, +, Ser109Glu, +, Gly110Glu, +, Trp112GlnVal103Ser, +, Asp105Glu, +, Gly108Glu, +, Val115ProAsp105Glu, +, Ser107Asp, +, Trp112Leu, +, Thr113GlyLeu104His, +, Asp105Glu, +, Asn106Ser, +, Ser107AspAsp105Glu, +, Ser107Glu, +, Ser109Asp, +, Val115GlnAsp105Glu, +, Ser107Glu, +, Ser109Glu, +, Thr113GlySer107Glu, +, Ser109Glu, +, Thr111Gln, +, Thr113GlnSer107Glu, +, Ser109Glu, +, Trp112Val, +, Val115ProSer107Glu, +, Ser109Glu, +, Trp112Ile, +, Val115GlnAsp105Glu, +, Ser109Glu, +, Gly110Gln, +, Val115ProLeu104Glu, +, Asp105Glu, +, Ser107Glu, +, Ala114GlyAsp105Glu, +, Asn106Glu, +, Gly108Pro, +, Ser109AspLeu104Asn, +, Asp105Glu, +, Gly110Asp, +, Ala114GlySer107Glu, +, Gly108Gln, +, Ser109Asp, +, Gly110AspGly108Gln, +, Gly110Glu, +, Trp112Asp, +, Val115GluVal103Asp, +, Leu104Ser, +, Asp105Glu, +, Val115GlnLeu104Glu, +, Asn106Glu, +, Gly110Glu, +, Val115AsnLeu104Asp, +, Gly110Glu, +, Thr111Ser, +, Trp112AspSer109Asp, +, Gly110Glu, +, Thr113Asn, +, Val115GluVal103Ser, +, Gly108Asp, +, Gly110Glu, +, Thr111GluLeu104Gly, +, Asn106Glu, +, Gly108Asn, +, Ser109GluVal103Asp, +, Leu104Gly, +, Thr111Glu, +, Val115Met
Table 10
Ring 3-single mutation varient
Leu134Ala
Leu134Asn
Leu134Asp
Leu134Cys
Leu134Gln
Leu134Glu
Leu134Gly
Leu134His
Leu134Ile
Leu134Met
Leu134Pro
Leu134Ser
Leu134Thr
Leu134Val
Gly135Asn
Gly135Asp
Gly135Gln
Gly135Glu
Gly135Pro
Gly135Ser
Gly136Asn
Gly136Asp
Gly136Gln
Gly136Glu
Gly136Pro
Gly136Ser
Thr137Asn
Thr137Asp
Thr137Gln
Thr137Glu
Thr137Gly
Thr137Pro
Thr137Ser
Val138Ala
Val138Asn
Val138Asp
Val138Cys
Val138Gln
Val138Glu
Val138Gly
Val138His
Val138Met
Val138Pro
Val138Ser
Val138Thr
Gly139Asn
Gly139Asp
Gly139Gln
Gly139Glu
Gly139Pro
Gly139Ser
Asn140Asp
Asn140Gln
Asn140Glu
Asn140Ser
Ser141Asp
Ser141Glu
Table 11
the two sudden change of ring 3-variant Leu134Val, +, Ser141AspLeu134Val, +, Thr137GluGly135Asn, +, Ser141AspGly135Ser, +, Thr137SerLeu134Met, +, Gly139AspLeu134Thr, +, Gly139GlnGly139Gln, +, Asn140GluGly139Pro, +, Ser141AspLeu134Glu, +, Val138AsnLeu134Asn, +, Val138AlaLeu134Ser, +, Asn140GluVal138Asn, +, Ser141AspGly135Glu, +, Val138SerLeu134Ile, +, Gly139GluLeu134Ile, +, Gly135AsnLeu134Met, +, Asn140AspGly136Ser, +, Gly139AspGly136Pro, +, Val138AsnLeu134Gly, +, Gly135ProLeu134Gly, +, Ser141GluGly135Pro, +, Gly139ProLeu134Thr, +, Gly139ProGly135Glu, +, Asn140SerThr137Gln, +, Gly139AspGly135Asp, +, Asn140SerLeu134Ser, +, Asn140AspGly136Gln, +, Gly139AspLeu134Pro, +, Ser141GluLeu134His, +, Asn140GlnLeu134Pro, +, Gly135GluGly135Pro, +, Gly136AspVal138Thr, +, Ser141AspVal138Pro, +, Ser141AspLeu134Gln, +, Thr137GluVal138Ser, +, Ser141AspVal138Thr, +, Asn140GlnLeu134Glu, +, Val138GlnGly139Asn, +, Ser141GluGly139Pro, +, Ser141GluGly135Gln, +, Gly139GluThr137Pro, +, Val138GlyGly135Asp, +, Gly136GlnGly135Asn, +, Val138ThrThr137Asn, +, Ser141GluGly135Pro, +, Val138GluGly135Glu, +, Thr137SerGly135Asp, +, Gly139ProLeu134Ala, +, Gly135GlnVal138Gln, +, Ser141AspGly135Ser, +, Gly139AspThr137Ser, +, Val138MetLeu134Ala, +, Gly136GlnLeu134Glu, +, Asn140GlnGly136Asn, +, Asn140GlnGly136Gln, +, Ser141AspVal138Ser, +, Ser141GluLeu134Thr, +, Thr137GluGly135Ser, +, Gly139ProVal138Cys, +, Gly139AspThr137Gly, +, Gly139Asp
Table 12
ring 3-three sudden change variant Gly135Ser, +, Val138Cys, +, Ser141AspGly135Gln, +, Thr137Glu, +, Val138CysLeu134Ser, +, Gly135Pro, +, Gly136GluLeu134Pro, +, Val138Cys, +, Asn140SerLeu134Val, +, Gly135Asp, +, Val138MetLeu134Pro, +, Gly135Pro, +, Gly139GluGly135Gln, +, Val138Asp, +, Gly139SerGly136Pro, +, Val138His, +, Ser141AspLeu134Val, +, Gly136Ser, +, Asn140AspThr137Asp, +, Val138Met, +, Gly139GlnLeu134Val, +, Gly136Pro, +, Thr137GlyGly135Gln, +, Val138Gln, +, Asn140AspLeu134His, +, Gly136Glu, +, Asn140GlnGly135Pro, +, Gly139Gln, +, Ser141AspGly136Asn, +, Val138Asn, +, Ser141AspGly135Asp, +, Val138Thr, +, Gly139GlnGly136Pro, +, Thr137Asp, +, Gly139SerLeu134Gly, +, Gly136Gln, +, Gly139SerLeu134Val, +, Gly135Glu, +, Thr137GlyLeu134Thr, +, Val138Gln, +, Gly139SerGly136Asp, +, Thr137Asn, +, Val138GlyGly135Asp, +, Val138Ser, +, Asn140GlnGly136Asn, +, Val138Glu, +, Asn140GlnLeu134Cys, +, Thr137Glu, +, Val138GlyLeu134Asn, +, Gly135Glu, +, Gly139SerGly135Ser, +, Val138His, +, Asn140GluLeu134Ala, +, Gly139Ser, +, Asn140GlnGly135Asp, +, Thr137Pro, +, Val138CysLeu134Cys, +, Val138Gly, +, Asn140AspLeu134Thr, +, Val138Ser, +, Gly139AspLeu134Cys, +, Thr137Gln, +, Ser141GluLeu134Val, +, Gly136Pro, +, Gly139GluLeu134Ala, +, Gly135Asn, +, Ser141GluGly136Gln, +, Thr137Gln, +, Val138ProLeu134Asp, +, Gly135Pro, +, Gly139SerGly135Ser, +, Val138Gly, +, Ser141AspLeu134Val, +, Thr137Asp, +, Gly139GlnLeu134His, +, Gly135Pro, +, Gly139GlnThr137Pro, +, Val138Gln, +, Asn140AspThr137Gln, +, Val138Cys, +, Gly139GluThr137Ser, +, Gly139Glu, +, Asn140GlnGly135Gln, +, Thr137Gln, +, Asn140AspGly135Gln, +, Thr137Gln, +, Val138AspLeu134His, +, Gly139Gln, +, Asn140AspLeu134Ala, +, Thr137Asn, +, Gly139GluVal138Pro, +, Gly139Pro, +, Asn140GlnGly135Asn, +, Asn140Ser, +, Ser141GluLeu134Ile, +, Gly135Asp, +, Val138CysThr137Gln, +, Gly139Ser, +, Asn140SerLeu134Ala, +, Gly136Pro, +, Asn140AspGly135Ser, +, Gly139Asp, +, Asn140SerLeu134Thr, +, Gly135Asn, +, Ser141GluLeu134Gly, +, Thr137Ser, +, Val138AlaLeu134Thr, +, Gly135Gln, +, Val138ProGly135Gln, +, Gly136Asp, +, Thr137SerGly135Ser, +, Val138Thr, +, Asn140AspLeu134Cys, +, Thr137Ser, +, Val138GluGly136Ser, +, Thr137Asn, +, Ser141AspLeu134Thr, +, Gly135Glu, +, Gly139GlnLeu134Thr, +, Gly135Asp, +, Thr137Ser
Table 13
ring 3-four sudden change variant Leu134Met, +, Thr137Pro, +, Asn140Ser, +, Ser141GluLeu134Asn, +, Gly136Pro, +, Thr137Ser, +, Val138GlnLeu134Gln, +, Gly136Gln, +, Val138Ser, +, Gly139SerGly135Glu, +, Gly136Asn, +, Thr137Pro, +, Asn140GlnLeu134Ser, +, Gly136Asn, +, Gly139Gln, +, Ser141GluLeu134Gln, +, Val138Pro, +, Gly139Ser, +, Ser141AspLeu134Pro, +, Gly135Asn, +, Thr137Glu, +, Asn140GlnGly135Asp, +, Thr137Gly, +, Val138Gln, +, Gly139SerLeu134Val, +, Gly135Asp, +, Thr137Asn, +, Asn140SerLeu134Thr, +, Gly135Glu, +, Gly136Ser, +, Thr137SerGly136Pro, +, Thr137Gln, +, Gly139Gln, +, Asn140GluLeu134His, +, Gly135Glu, +, Val138Asn, +, Asn140GlnLeu134Gln, +, Gly135Ser, +, Thr137Asn, +, Ser141GluGly135Gln, +, Gly139Asn, +, Asn140Gln, +, Ser141AspThr137Gln, +, Val138His, +, Gly139Asn, +, Ser141GluLeu134Thr, +, Gly135Gln, +, Val138Thr, +, Asn140AspLeu134Met, +, Gly135Glu, +, Thr137Ser, +, Val138SerVal138Thr, +, Gly139Ser, +, Asn140Ser, +, Ser141GluLeu134Met, +, Gly136Pro, +, Val138Cys, +, Gly139ProLeu134His, +, Gly136Pro, +, Thr137Gln, +, Gly139GluGly135Asn, +, Gly136Gln, +, Val138Cys, +, Ser141GluLeu134Asn, +, Thr137Ser, +, Val138Gln, +, Ser141AspGly135Gln, +, Gly136Pro, +, Thr137Asn, +, Asn140SerGly135Asn, +, Gly139Ser, +, Asn140Gln, +, Ser141AspLeu134Met, +, Gly136Pro, +, Val138Met, +, Ser141GluLeu134Cys, +, Thr137Gln, +, Val138Pro, +, Ser141AspGly136Asn, +, Thr137Gln, +, Gly139Asn, +, Asn140SerLeu134Asn, +, Thr137Ser, +, Gly139Ser, +, Asn140AspGly135Asp, +, Gly136Asp, +, Val138Met, +, Asn140SerGly135Glu, +, Gly136Asp, +, Val138His, +, Gly139GlnLeu134Ser, +, Gly136Glu, +, Thr137Glu, +, Val138ThrLeu134Thr, +, Val138Gln, +, Asn140Glu, +, Ser141GluGly135Gln, +, Thr137Asn, +, Asn140Glu, +, Ser141GluGly135Gln, +, Thr137Gly, +, Val138Asp, +, Gly139AspLeu134Thr, +, Gly135Glu, +, Gly136Asp, +, Thr137AspVal138Asn, +, Gly139Asp, +, Asn140Glu, +, Ser141AspLeu134Ile, +, Gly139Glu, +, Asn140Asp, +, Ser141AspGly136Pro, +, Gly139Glu, +, Asn140Glu, +, Ser141AspLeu134Gln, +, Gly139Asp, +, Asn140Asp, +, Ser141GluLeu134Val, +, Gly136Glu, +, Val138Asp, +, Asn140GlnGly136Asp, +, Thr137Gln, +, Val138Asp, +, Gly139AsnGly136Glu, +, Thr137Glu, +, Val138His, +, Gly139AspLeu134His, +, Thr137Gln, +, Val138Glu, +, Asn140GluLeu134Gly, +, Gly135Ser, +, Thr137Glu, +, Gly139GluLeu134Gln, +, Gly135Pro, +, Thr137Asp, +, Gly139AspLeu134His, +, Gly135Asn, +, Thr137Asp, +, Gly139GluLeu134Val, +, Gly135Glu, +, Thr137Asp, +, Gly139GlnGly135Asn, +, Thr137Ser, +, Gly139Asp, +, Ser141AspLeu134Cys, +, Thr137Asn, +, Gly139Glu, +, Ser141AspLeu134Ile, +, Thr137Pro, +, Gly139Asp, +, Ser141AspLeu134Thr, +, Val138Asn, +, Gly139Glu, +, Ser141AspGly135Pro, +, Thr137Gly, +, Gly139Glu, +, Ser141AspGly136Ser, +, Val138Ala, +, Gly139Glu, +, Ser141GluLeu134Thr, +, Gly139Asp, +, Asn140Ser, +, Ser141AspGly135Ser, +, Thr137Gly, +, Gly139Glu, +, Ser141AspLeu134Met, +, Gly135Asn, +, Gly139Asp, +, Ser141GluThr137Pro, +, Val138Gly, +, Gly139Asp, +, Ser141AspGly136Glu, +, Thr137Pro, +, Val138Gln, +, Gly139AspThr137Asn, +, Val138Glu, +, Gly139Asp, +, Ser141AspLeu134Thr, +, Val138Glu, +, Gly139Glu, +, Ser141Glu
Table 14
Ring 4-single mutation varient
Gly162Asn
Gly162Asp
Gly162Gln
Gly162Glu
Gly162Pro
Gly162Ser
Asn163Asp
Asn163Gln
Asn163Glu
Asn163Ser
Ala164Asn
Ala164Asp
Ala164Gln
Ala164Glu
Ala164Gly
Ala164His
Ala164Pro
Ala164Ser
Ala164Thr
Gly165Asn
Gly165Asp
Gly165Gln
Gly165Glu
Gly165Pro
Gly165Ser
Asn166Asp
Asn166Gln
Asn166Glu
Asn166Ser
Thr167Asn
Thr167Asp
Thr167Gln
Thr167Glu
Thr167Gly
Thr167Pro
Thr167Ser
Ala168Asn
Ala168Asp
Ala168Gln
Ala168Glu
Ala168Gly
Ala168His
Ala168Pro
Ala168Ser
Ala168Thr
Pro169Asn
Pro169Asp
Pro169Gln
Pro169Glu
Pro169Gly
Pro169Ser
Asn170Asp
Asn170Gln
Asn170Glu
Asn170Ser
Tyr171Ala
Tyr171Asn
Tyr171Asp
Tyr171Cys
Tyr171Gln
Tyr171Glu
Tyr171Gly
Tyr171His
Tyr171Ile
Tyr171Leu
Tyr171Met
Tyr171Pro
Tyr171Ser
Tyr171Thr
Tyr171Val
Table 15
the two sudden change of ring 4-variant Ala164Gln, +, Pro169GluAsn163Asp, +, Thr167SerAla164Pro, +, Ala168AspAla164Gln, +, Asn166SerGly165Asp, +, Thr167ProAla164Gln, +, Ala168SerGly165Gln, +, Asn166GlnGly162Gln, +, Asn163GluGly165Gln, +, Thr167GluGly165Ser, +, Ala168GlnAla164Gln, +, Ala168GluAla164His, +, Tyr171MetGly165Pro, +, Pro169GlnGly165Gln, +, Ala168ProGly162Pro, +, Ala164GlyThr167Pro, +, Asn170SerAsn163Gln, +, Tyr171HisAsn163Ser, +, Ala164GlnAla164Asp, +, Asn166GlnGly165Asn, +, Tyr171IleAla168Asp, +, Asn170GlnAsn166Asp, +, Ala168GlyAsn163Glu, +, Thr167SerAsn166Glu, +, Ala168SerGly162Gln, +, Ala168GluGly162Asn, +, Asn170SerAsn163Gln, +, Ala168HisThr167Pro, +, Ala168ThrGly162Asn, +, Gly165GluAsn166Glu, +, Tyr171ProAla168Asn, +, Asn170GlnGly162Glu, +, Thr167SerThr167Asp, +, Tyr171ValGly162Asp, +, Ala168HisGly165Ser, +, Ala168GluThr167Asp, +, Tyr171MetAla168Thr, +, Pro169GlyGly165Ser, +, Pro169GluGly162Glu, +, Ala164ThrAla168Ser, +, Tyr171AspAsn163Ser, +, Gly165ProAla168Asn, +, Tyr171SerAla164Gln, +, Gly165GlnThr167Asp, +, Asn170SerGly165Ser, +, Asn170GlnThr167Gly, +, Tyr171GluGly162Asn, +, Tyr171GlnGly165Asn, +, Asn166GluAla168Thr, +, Tyr171GluGly165Ser, +, Asn166GluThr167Gly, +, Ala168ThrAsn166Asp, +, Ala168AsnPro169Glu, +, Tyr171ValGly162Glu, +, Asn170SerGly162Ser, +, Pro169GlyAla164Asn, +, Asn166GluThr167Gly, +, Asn170AspThr167Glu, +, Asn170SerAsn163Asp, +, Ala164GlnGly165Gln, +, Pro169Glu
Table 16
ring 4-three sudden change variant Ala164Gly, +, Gly165Glu, +, Thr167SerGly162Asn, +, Ala164Thr, +, Asn166AspAla164Asn, +, Gly165Asp, +, Pro169GlnGly165Pro, +, Thr167Asn, +, Pro169GluAla168Gly, +, Pro169Gly, +, Asn170AspGly162Asp, +, Gly165Pro, +, Ala168SerGly165Asp, +, Thr167Asn, +, Tyr171GlyThr167Ser, +, Pro169Asn, +, Tyr171ThrAsn166Ser, +, Ala168Gly, +, Tyr171IleGly165Gln, +, Thr167Pro, +, Ala168GluGly162Ser, +, Asn163Asp, +, Gly165GlnGly165Glu, +, Thr167Gly, +, Ala168SerThr167Gly, +, Ala168Asp, +, Tyr171ValAsn163Ser, +, Gly165Gln, +, Ala168AspAsn163Asp, +, Ala164Gly, +, Gly165AsnAla164Gln, +, Pro169Ser, +, Asn170GlnAla164His, +, Thr167Gln, +, Pro169GlyThr167Ser, +, Ala168Asn, +, Tyr171AsnGly162Asp, +, Gly165Ser, +, Ala168AsnGly162Pro, +, Asn163Gln, +, Tyr171ValAsn166Glu, +, Ala168Ser, +, Asn170GlnThr167Pro, +, Pro169Ser, +, Tyr171HisGly162Gln, +, Asn163Gln, +, Gly165AspAla164Ser, +, Thr167Ser, +, Ala168GluThr167Gln, +, Pro169Glu, +, Asn170GlnAsn163Gln, +, Pro169Asn, +, Asn170GlnGly162Glu, +, Ala168Gln, +, Asn170GlnAla164Gly, +, Gly165Ser, +, Asn166AspAla164Ser, +, Ala168Gly, +, Asn170GlnAsn163Glu, +, Ala164Asn, +, Ala168SerThr167Ser, +, Pro169Glu, +, Tyr171SerAla168Glu, +, Pro169Gln, +, Tyr171IleGly162Pro, +, Ala164Pro, +, Tyr171ProGly162Pro, +, Asn166Ser, +, Pro169GluAla164Gly, +, Ala168Asn, +, Tyr171SerAla164Thr, +, Asn170Asp, +, Tyr171LeuAsn163Gln, +, Thr167Glu, +, Pro169SerAsn166Asp, +, Ala168Gln, +, Tyr171ProGly162Asn, +, Ala164Glu, +, Tyr171AlaAsn166Glu, +, Thr167Gln, +, Ala168ProAla164Pro, +, Ala168Gln, +, Asn170AspAla164Thr, +, Gly165Gln, +, Ala168AspAla164Ser, +, Ala168Gly, +, Asn170GluAla164His, +, Gly165Glu, +, Tyr171MetAla164Gln, +, Gly165Asp, +, Asn166GlnGly162Gln, +, Thr167Asn, +, Ala168AsnAla168His, +, Pro169Gln, +, Tyr171GluAla164Gln, +, Asn166Gln, +, Tyr171ValGly162Pro, +, Ala164Ser, +, Asn170GlnThr167Glu, +, Ala168Gly, +, Asn170SerThr167Ser, +, Pro169Gly, +, Asn170SerAsn163Glu, +, Asn166Ser, +, Ala168SerAsn163Gln, +, Ala168Glu, +, Tyr171AlaThr167Ser, +, Ala168Ser, +, Asn170AspGly165Asp, +, Asn166Glu, +, Tyr171ProAsn163Asp, +, Ala164Asp, +, Thr167SerAla164Asp, +, Gly165Glu, +, Asn166GlnGly162Ser, +, Ala164Glu, +, Gly165AspGly165Asn, +, Asn170Glu, +, Tyr171GluGly165Pro, +, Asn170Glu, +, Tyr171Glu
Table 17
ring 4-four sudden change variant Ala164Asn, +, Asn166Asp, +, Thr167Asn, +, Ala168GlnGly162Asn, +, Asn163Gln, +, Ala164Asn, +, Asn170GluAla164Thr, +, Asn166Ser, +, Ala168Asn, +, Pro169GluAla164Gln, +, Pro169Asn, +, Asn170Glu, +, Tyr171ThrAsn163Ser, +, Ala164Thr, +, Thr167Asp, +, Tyr171ThrThr167Ser, +, Pro169Ser, +, Asn170Asp, +, Tyr171SerGly162Asn, +, Thr167Gly, +, Pro169Gln, +, Tyr171SerGly162Pro, +, Asn163Ser, +, Ala168Glu, +, Tyr171ValAsn163Gln, +, Ala168Asp, +, Pro169Gln, +, Asn170GlnAla164Asn, +, Gly165Ser, +, Pro169Gln, +, Tyr171IleGly162Glu, +, Thr167Gln, +, Ala168Ser, +, Tyr171SerGly165Ser, +, Ala168Gly, +, Asn170Asp, +, Tyr171LeuAla164His, +, Gly165Asp, +, Asn166Gln, +, Tyr171ThrAsn163Gln, +, Ala164Ser, +, Asn166Ser, +, Ala168GluAsn166Asp, +, Thr167Asn, +, Asn170Ser, +, Tyr171ThrGly162Asp, +, Gly165Gln, +, Asn170Ser, +, Tyr171GlnGly162Pro, +, Ala168Asn, +, Pro169Glu, +, Tyr171GlyAsn166Gln, +, Thr167Gln, +, Ala168Thr, +, Asn170AspAsn163Gln, +, Thr167Asp, +, Ala168Ser, +, Tyr171ProAla164Pro, +, Thr167Glu, +, Pro169Ser, +, Tyr171ValGly165Asn, +, Asn166Gln, +, Pro169Gly, +, Asn170AspAsn166Ser, +, Thr167Pro, +, Ala168Asn, +, Asn170GluAla164Gly, +, Ala168Asn, +, Pro169Asp, +, Tyr171AlaAla164Gln, +, Gly165Gln, +, Thr167Ser, +, Pro169GluAsn163Glu, +, Gly165Ser, +, Thr167Gln, +, Ala168ThrGly162Pro, +, Ala164Thr, +, Thr167Ser, +, Pro169GlnGly162Gln, +, Asn163Glu, +, Gly165Gln, +, Thr167ProAsn163Ser, +, Pro169Gly, +, Asn170Glu, +, Tyr171SerAsn163Gln, +, Gly165Ser, +, Asn170Asp, +, Tyr171LeuAla164His, +, Gly165Pro, +, Pro169Ser, +, Asn170GlnGly162Pro, +, Asn166Gln, +, Ala168Asn, +, Asn170GluAsn163Gln, +, Gly165Pro, +, Thr167Ser, +, Tyr171GlyAsn163Gln, +, Gly165Asn, +, Asn166Ser, +, Tyr171CysAsn163Asp, +, Gly165Pro, +, Asn166Ser, +, Tyr171GlyAla164Pro, +, Thr167Pro, +, Pro169Glu, +, Asn170SerAsn163Asp, +, Ala164Glu, +, Pro169Gln, +, Tyr171HisAsn163Glu, +, Ala164Glu, +, Ala168Gly, +, Tyr171HisThr167Asp, +, Ala168Glu, +, Pro169Gln, +, Asn170SerAla164Asp, +, Gly165Asp, +, Ala168Asn, +, Pro169GlnGly162Ser, +, Ala164Gly, +, Asn170Asp, +, Tyr171GluAsn163Gln, +, Thr167Asn, +, Ala168Asp, +, Pro169GluAsn163Ser, +, Gly165Pro, +, Ala168Asp, +, Pro169GluGly165Ser, +, Ala168Asp, +, Pro169Glu, +, Asn170SerAsn166Gln, +, Ala168Gln, +, Pro169Asp, +, Asn170AspAla164Gly, +, Thr167Gly, +, Pro169Glu, +, Asn170AspGly162Pro, +, Ala164Gly, +, Pro169Asp, +, Asn170GluAla164Pro, +, Thr167Glu, +, Ala168Asp, +, Pro169AspGly162Asp, +, Asn163Gln, +, Ala168His, +, Asn170AspGly162Glu, +, Ala164Ser, +, Asn166Ser, +, Asn170GluGly162Glu, +, Ala164Ser, +, Asn166Gln, +, Asn170GluThr167Asp, +, Ala168His, +, Pro169Glu, +, Tyr171ProAsn163Glu, +, Ala164His, +, Gly165Asp, +, Asn166GlnAsn163Asp, +, Ala164Gln, +, Gly165Asp, +, Asn166SerAsn163Glu, +, Ala164Asp, +, Gly165Gln, +, Ala168AspGly162Glu, +, Ala164Glu, +, Asn166Ser, +, Pro169AspAla164Glu, +, Asn166Asp, +, Asn170Ser, +, Tyr171GlyAla164Glu, +, Gly165Gln, +, Asn166Glu, +, Tyr171CysAla164Asp, +, Asn166Glu, +, Thr167Asn, +, Pro169AsnThr167Asp, +, Pro169Glu, +, Asn170Glu, +, Tyr171SerAsn166Asp, +, Thr167Ser, +, Ala168Asp, +, Tyr171His
Table 18
Ring 5-single mutation varient
Ser191Asp
Ser191Glu
Ser192Asp
Ser192Glu
Phe193Ala
Phe193Asn
Phe193Asp
Phe193Cys
Phe193Gln
Phe193Glu
Phe193Gly
Phe193His
Phe193Ile
Phe193Leu
Phe193Met
Phe193Pro
Phe193Ser
Phe193Thr
Phe193Tyr
Phe193Val
Ser194Asp
Ser194Glu
Thr195Asn
Thr195Asp
Thr195Gln
Thr195Glu
Thr195Gly
Thr195Pro
Thr195Ser
Table 19
the two sudden change of ring 5-variant Ser192Asp, +, Phe193SerSer192Asp, +, Phe193MetSer191Glu, +, Phe193AsnSer191Asp, +, Phe193IleSer191Glu, +, Phe193GlnSer191Asp, +, Thr195SerPhe193Gly, +, Thr195AspSer192Asp, +, Phe193CysSer191Glu, +, Thr195ProSer191Glu, +, Phe193MetPhe193Thr, +, Thr195GluSer192Asp, +, Thr195GlnPhe193Asp, +, Thr195AsnSer191Asp, +, Phe193GlnPhe193Gly, +, Thr195ProSer192Asp, +, Thr195SerSer191Glu, +, Phe193IlePhe193Gln, +, Thr195AsnSer191Glu, +, Thr195GlySer191Glu, +, Phe193HisSer191Asp, +, Phe193LeuSer192Glu, +, Phe193ProPhe193His, +, Thr195GluSer192Asp, +, Thr195GlySer192Glu, +, Phe193AlaSer192Glu, +, Phe193ValSer192Asp, +, Phe193LeuSer192Glu, +, Phe193AsnPhe193Tyr, +, Thr195SerPhe193His, +, Thr195AsnSer192Glu, +, Thr195SerPhe193Ile, +, Thr195GluPhe193Val, +, Thr195AsnPhe193Met, +, Thr195GlnSer191Asp, +, Thr195ProSer192Glu, +, Phe193TyrPhe193Ser, +, Thr195AsnSer192Glu, +, Phe193GlnSer191Asp, +, Phe193SerSer192Asp, +, Phe193IleSer192Asp, +, Phe193HisSer192Asp, +, Phe193GlySer191Glu, +, Phe193SerSer192Glu, +, Thr195GlnSer191Glu, +, Thr195SerSer191Asp, +, Thr195AsnSer191Glu, +, Phe193ValPhe193Tyr, +, Thr195AspPhe193His, +, Thr195SerSer192Glu, +, Phe193IlePhe193Met, +, Thr195GlySer191Glu, +, Phe193TyrSer191Asp, +, Thr195GlnSer192Asp, +, Phe193AsnSer192Asp, +, Phe193ThrSer192Glu, +, Phe193CysPhe193Asp, +, Thr195GlnPhe193Val, +, Thr195GlnSer192Glu, +, Phe193ThrPhe193Leu, +, Thr195Glu
Table 20
ring 5-three sudden change variant Ser192Glu, +, Phe193Thr, +, Thr195GlySer191Glu, +, Phe193His, +, Thr195SerSer192Asp, +, Phe193Leu, +, Thr195AsnSer191Asp, +, Phe193Ala, +, Thr195SerSer192Asp, +, Phe193Val, +, Thr195GlnSer191Asp, +, Phe193Ser, +, Thr195ProSer191Asp, +, Phe193Ile, +, Thr195GlySer192Glu, +, Phe193His, +, Thr195GlySer192Glu, +, Phe193Leu, +, Thr195AsnSer192Asp, +, Phe193Gly, +, Thr195GlnSer192Asp, +, Phe193Ile, +, Thr195ProSer191Glu, +, Phe193Asn, +, Thr195SerSer192Asp, +, Phe193Met, +, Thr195AsnSer191Glu, +, Phe193Gly, +, Thr195AsnSer192Glu, +, Phe193His, +, Thr195AsnSer192Asp, +, Phe193Met, +, Thr195ProSer191Glu, +, Phe193Leu, +, Thr195AsnSer191Glu, +, Phe193Met, +, Thr195AsnSer192Glu, +, Phe193Ala, +, Thr195GlnSer191Glu, +, Phe193Tyr, +, Thr195GlySer192Asp, +, Phe193Ala, +, Thr195GlySer191Glu, +, Phe193Met, +, Thr195GlySer192Glu, +, Phe193Thr, +, Thr195GlnSer191Asp, +, Phe193Asn, +, Thr195GlySer192Glu, +, Phe193Asn, +, Thr195SerSer192Asp, +, Phe193Ser, +, Thr195GlySer192Glu, +, Phe193Leu, +, Thr195ProSer191Asp, +, Phe193Cys, +, Thr195GlySer191Asp, +, Ser192Asp, +, Phe193TyrSer191Asp, +, Ser192Asp, +, Phe193GlySer191Asp, +, Ser192Glu, +, Phe193MetSer191Asp, +, Ser192Glu, +, Thr195GlnSer191Glu, +, Ser192Asp, +, Phe193ValSer191Glu, +, Ser192Glu, +, Phe193ThrSer191Glu, +, Ser192Asp, +, Phe193ThrSer191Asp, +, Ser192Asp, +, Thr195GlySer191Glu, +, Ser192Glu, +, Phe193AsnSer191Asp, +, Ser192Glu, +, Phe193AlaSer191Asp, +, Ser192Asp, +, Phe193AsnSer191Asp, +, Ser192Asp, +, Phe193ProSer191Asp, +, Ser192Glu, +, Phe193ThrSer191Asp, +, Ser192Asp, +, Thr195AsnSer191Asp, +, Ser192Asp, +, Thr195GlnSer191Glu, +, Ser192Asp, +, Phe193AsnSer191Glu, +, Ser192Glu, +, Phe193GlnSer191Glu, +, Ser192Asp, +, Phe193LeuSer191Asp, +, Ser192Asp, +, Thr195SerSer191Asp, +, Ser192Glu, +, Phe193SerSer191Glu, +, Ser192Asp, +, Phe193TyrSer191Asp, +, Ser192Asp, +, Phe193ThrSer191Asp, +, Ser192Glu, +, Phe193ProSer191Glu, +, Ser192Asp, +, Phe193IleSer191Asp, +, Ser192Glu, +, Phe193TyrSer191Glu, +, Ser192Glu, +, Phe193TyrSer191Asp, +, Ser192Asp, +, Phe193SerSer191Glu, +, Ser192Glu, +, Thr195ProSer191Asp, +, Ser192Glu, +, Thr195SerSer191Glu, +, Ser192Asp, +, Phe193MetSer191Asp, +, Ser192Glu, +, Thr195ProSer191Glu, +, Ser192Asp, +, Phe193His
Table 21
ring 5-four sudden change variant Ser191Asp, +, Ser192Glu, +, Phe193Gly, +, Thr195GlnSer191Glu, +, Ser192Asp, +, Phe193His, +, Thr195GlySer191Glu, +, Ser192Glu, +, Phe193Cys, +, Thr195ProSer191Asp, +, Ser192Glu, +, Phe193Cys, +, Thr195GlnSer191Asp, +, Ser192Glu, +, Phe193Thr, +, Thr195ProSer191Glu, +, Ser192Glu, +, Phe193Val, +, Thr195AsnSer191Asp, +, Ser192Glu, +, Phe193Val, +, Thr195AsnSer191Glu, +, Ser192Glu, +, Phe193Leu, +, Thr195SerSer191Glu, +, Ser192Asp, +, Phe193Cys, +, Thr195GlnSer191Glu, +, Ser192Asp, +, Phe193Pro, +, Thr195ProSer191Glu, +, Ser192Asp, +, Phe193Ser, +, Thr195GlySer191Glu, +, Ser192Asp, +, Phe193Pro, +, Thr195AsnSer191Glu, +, Ser192Glu, +, Phe193Ser, +, Thr195ProSer191Glu, +, Ser192Asp, +, Phe193Ala, +, Thr195GlySer191Asp, +, Ser192Glu, +, Phe193His, +, Thr195AsnSer191Asp, +, Ser192Glu, +, Phe193Asn, +, Thr195AsnSer191Glu, +, Ser192Glu, +, Phe193Gln, +, Thr195SerSer191Glu, +, Ser192Glu, +, Phe193Thr, +, Thr195GlnSer191Glu, +, Ser192Glu, +, Phe193Asn, +, Thr195GlnSer191Glu, +, Ser192Glu, +, Phe193Tyr, +, Thr195SerSer191Asp, +, Ser192Glu, +, Phe193Ile, +, Thr195ProSer191Glu, +, Ser192Asp, +, Phe193Val, +, Thr195GlnSer191Glu, +, Ser192Asp, +, Phe193Val, +, Thr195AsnSer191Asp, +, Ser192Glu, +, Phe193Tyr, +, Thr195SerSer191Asp, +, Ser192Glu, +, Phe193Ala, +, Thr195SerSer191Glu, +, Ser192Glu, +, Phe193His, +, Thr195AsnSer191Asp, +, Ser192Asp, +, Phe193Pro, +, Thr195AsnSer191Asp, +, Ser192Asp, +, Phe193Gln, +, Thr195SerSer191Asp, +, Ser192Asp, +, Phe193Leu, +, Thr195AsnSer191Asp, +, Ser192Glu, +, Phe193Val, +, Thr195GlnSer191Glu, +, Ser192Glu, +, Phe193Gly, +, Thr195GlySer191Glu, +, Ser192Glu, +, Phe193Thr, +, Thr195ProSer191Glu, +, Ser192Glu, +, Phe193Thr, +, Thr195GlySer191Glu, +, Ser192Asp, +, Phe193Ile, +, Thr195SerSer191Glu, +, Ser192Glu, +, Phe193Ile, +, Thr195GlySer191Asp, +, Ser192Asp, +, Phe193Pro, +, Thr195ProSer191Asp, +, Ser192Asp, +, Phe193Ile, +, Thr195GlySer191Glu, +, Ser192Asp, +, Phe193Thr, +, Thr195GlySer191Asp, +, Ser192Glu, +, Phe193Ser, +, Thr195GlySer191Glu, +, Ser192Asp, +, Phe193Tyr, +, Thr195SerSer191Asp, +, Ser192Asp, +, Phe193Thr, +, Thr195GlnSer191Asp, +, Ser192Glu, +, Phe193Ser, +, Thr195GlnSer191Glu, +, Ser192Glu, +, Phe193His, +, Thr195SerSer191Glu, +, Ser192Asp, +, Phe193Leu, +, Thr195AsnSer191Asp, +, Ser192Glu, +, Phe193Leu, +, Thr195ProSer191Asp, +, Ser192Asp, +, Phe193Ile, +, Thr195ProSer191Asp, +, Ser192Asp, +, Phe193Tyr, +, Thr195SerSer191Asp, +, Ser192Glu, +, Phe193Ile, +, Thr195GlnSer191Asp, +, Ser192Glu, +, Phe193Pro, +, Thr195SerSer191Asp, +, Ser192Glu, +, Phe193Leu, +, Thr195GlnSer191Glu, +, Ser192Asp, +, Phe193Asn, +, Thr195SerSer191Glu, +, Ser192Glu, +, Phe193Ser, +, Thr195AsnSer191Asp, +, Ser192Asp, +, Phe193Glu, +, Thr195GlnSer191Asp, +, Ser192Glu, +, Phe193Glu, +, Thr195ProSer191Glu, +, Ser192Asp, +, Phe193Glu, +, Thr195GlnSerl91Glu, +, Ser192Glu, +, Phe193Glu, +, Thr195GlySer191Glu, +, Ser192Glu, +, Phe193Asp, +, Thr195GlySer191Asp, +, Ser192Asp, +, Phe193Glu, +, Thr195SerSer191Glu, +, Ser192Asp, +, Phe193Asp, +, Thr195ProSer191Glu, +, Ser192Glu, +, Phe193Asp, +, Thr195Gln
Table 22
Ring 6-single mutation varient
Ala204Asn
Ala204Asp
Ala204Gln
Ala204Glu
Ala204Gly
Ala204His
Ala204Pro
Ala204Ser
Ala204Thr
Pro205Asn
Pro205Asp
Pro205Gln
Pro205Glu
Pro205Gly
Pro205Ser
Gly206Asn
Gly206Asp
Gly206Gln
Gly206Glu
Gly206Pro
Gly206Ser
Ser207Asp
Ser207Glu
Trp208Ala
Trp208Asn
Trp208Asp
Trp208Cys
Trp208Gln
Trp208Glu
Trp208Gly
Trp208His
Trp208Ile
Trp208Leu
Trp208Met
Trp208Phe
Trp208Pro
Trp208Ser
Trp208Thr
Trp208Tyr
Trp208Val
Ile209Ala
Ile209Asn
Ile209Asp
Ile209Cys
Ile209Gln
Ile209Glu
Ile209Gly
Ile209His
Ile209Leu
Ile209Met
Ile209Pro
Ile209Ser
Ile209Thr
Ile209Val
Tyr210Ala
Tyr210Asn
Tyr210Asp
Tyr210Cys
Tyr210Gln
Tyr210Glu
Tyr210Gly
Tyr210His
Tyr210Ile
Tyr210Leu
Tyr210Met
Tyr210Pro
Tyr210Ser
Tyr210Thr
Tyr210Val
Ser211Asp
Ser211Glu
Thr212Asn
Thr212Asp
Thr212Gln
Thr212Glu
Thr212Gly
Thr212Pro
Thr212Ser
Tyr213Ala
Tyr213Asn
Tyr213Asp
Tyr213Cys
Tyr213Gln
Tyr213Glu
Tyr213Gly
Tyr213His
Tyr213Ile
Tyr213Leu
Tyr213Met
Tyr213Pro
Tyr213Ser
Tyr213Thr
Tyr213Val
Pro214Asn
Pro214Asp
Pro214Gln
Pro214Glu
Pro214Gly
Pro214Ser
Thr215Asn
Thr215Asp
Thr215Gln
Thr215Glu
Thr215Gly
Thr215Pro
Thr215Ser
Ser216Asp
Ser216Glu
Thr217Asn
Thr217Asp
Thr217Gln
Thr217Glu
Thr217Gly
Thr217Pro
Thr217Ser
Tyr218Ala
Tyr218Asn
Tyr218Asp
Tyr218Cys
Tyr218Gln
Tyr218Glu
Tyr218Gly
Tyr218His
Tyr218Ile
Tyr218Leu
Tyr218Met
Tyr218Pro
Tyr218Ser
Tyr218Thr
Tyr218Val
Ala219Asn
Ala219Asp
Ala219Gln
Ala219Glu
Ala219Gly
Ala219His
Ala219Pro
Ala219Ser
Ala219Thr
Ser220Asp
Ser220Glu
Leu221Ala
Leu221Asn
Leu221Asp
Leu221Cys
Leu221Gln
Leu221Glu
Leu221Gly
Leu221His
Leu221Ile
Leu221Met
Leu221Pro
Leu221Ser
Leu221Thr
Leu221Val
Ser222Asp
Ser222Glu
Gly223Asn
Gly223Asp
Gly223Gln
Gly223Glu
Gly223Pro
Gly223Ser
Thr224Asn
Thr224Asp
Thr224Gln
Thr224Glu
Thr224Gly
Thr224Pro
Thr224Ser
Direction will be connected at a distance of two-way with negative electrode plate or the unidirectional conducting of the positive electrode plate of d> = 0 respectively.The positive electrode plate of induced electromotive force power supply and induced charge generation electric organ and the length of negative electrode plate or width or thickness are than the positive electrode plate of permanent electric field and negative electrode plate is little or equate greatly or preferably. induced electric field induced charge generator of the positive electrode plate and a negative electrode plate in the longitudinal direction or the width direction of the One end or both ends, respectively, of the induced electric field and the induced electromotive force power generator of the charge generating positive electrode plate and the negative electrode plates parallel to the coincident or parallel connection or docking coincident or conduction or induction field is formed integrally induced charge generator The positive electrode plate negatively charged plate inside the plane and the induced electromotive force power and charge generating generators positive electrode plate inside the plane were negative electrode plate inside the power supply and induced charge flow is unidirectional conducting positive electrode plate close to the negative electrode plate lateral conduction Connect or made into one. Be be positioned between the permanent electric field positive electrode any solid of any solid negative electrode or the parallel metal conductor utmost point inner or inside and outside can be respectively under the induction of permanent electric field, induce induced positive and induction negative electrical charge, can be from the conical surface metallic conductor tip of positive electrode plate and negative electrode plate or the wedge metal conductor tip escape the emission induced charge and the negative electrical charge of inducting automatically present rectangle or the taper of single head single face or single head single face wedge shape or two-sided taper of single head or the two-sided wedge shape of single head with parallel with negative electrode plate or the uneven cross section of permanent electric field positive electrode plate respectively, or single head single face needle point shape or single head two-sided needle point shape or the taper of double end single face or the two-sided wedge shape of double end or the two-sided needle point shape of double end or how much conductors of the two-sided taper of double end or any geometry be to solid or a pair of not parallel or parallel metal conductor plate, a termination or the two ends of long with the positive electrode plate of induction field charge inducing the generator respectively or cross direction of one or two positive electrode plate of induced electromotive force power supply and induced charge generation electric organ and one or two negative electrode plate and negative electrode plate is long or a termination of cross direction or parallel coincidences of two ends dock to be connected and lead or make one.The taper of positive electrode plate and negative electrode plate, wedge shape, needle point shape single face angle opposite face towards or opposing towards or the center symmetry towards, or the axle center symmetry towards, the taper of positive electrode plate and negative electrode plate, wedge shape pin, pointed two-sided angle, opposite face towards or opposing towards or the axle center symmetry towards, or the center symmetry is filled dielectric or is not filled dielectric except that the passage of reserving the most advanced and sophisticated emission travel path of escaping of induced charge metallic conductor towards, two parallel-plate outsides.Two relative parallel planes of positive electrode plate and negative electrode plate are close to fully mutually that conducting is connected or at a distance of spacing d> = 0, the positive electrode plate of induced electromotive force power supply and induced charge generation electric organ and negative electrode plate respectively the length overall of the positive electrode plate with the charge inducing generator after butt joint is connected conducting or makes one with negative electrode plate, beam overall, total thickness can be respectively than permanent electric field positive electrode plate and the permanent length and width of electric field negative electrode plate and thick either large or small or equal.EEBG01-EEBG02-EEBG03-EEBG04-EEBG05-EEBG06-EEBG07-EEBG08-EEBG09-EEBG10-EEBG11-EEBG12-EEBG13 -EEBG14-EEBG15-EEBG16-EEBG17-EEBG18-EEBG19-EEBG20-HHBG01-HHBG02-HHBG03-HHBG04 permanent induction electromagnetic field change-section conductor charge automatic escape emission power generator, characteristics of principle and shape structure general technical feature at first be to use permanent electric field, the secondth, the electromagnetic field inducing of the permanent electric field of application, the 3rd is that the application permanent electro magnetic field is that the mobile device of the inner unidirectional conducting of charge inducing generator and charge inducing power supply produces the principle that electromagnetic induction is isolated positive and negative charge inducing afterwards to the metallic conductor that is arranged in the permanent electric field, the 4th be make to adopt variable-section variable dimension awl wedge shape list or double end list double inclined plane does not wait or etc. gradient metallic conductor tip be induced electromotive force power supply and induced charge generation electric organ, escape and launch charge theory in the tip of induced charge escape reflector, the 5th is to use the charging photocell or friction produces electricity battery, charging capacitor, the moving forever power supply of charging environment friendly, the charge switch power-off switch, the moving forever amplifying type charger of forming of the moving forever permanent electric field of power supply waits and guarantees moving forever continuously output induced charge of moving forever power supply and electric energy energy.The induced electromotive force ε of induced electromotive force power supply and induced charge generation electric organ
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42Thr212Gln?+?Ala219GluAla204Gly?+?Trp208GlnAla204Thr?+?Ser216AspThr212Gln?+?Tyr218GlnSer207Glu?+?Leu221MetThr215Pro?+?Gly223GlnAla204Gly?+?Ser216AspTyr210Asp?+?Ala219HisIle209Gln?+?Tyr218AlaIle209Ala?+?Ala219ProAla204Asn?+?Ser222GluTyr210Asp?+?Tyr213AlaTyr218Leu?+?Thr224GluTyr218Asn?+?Ser220GluTrp208Met?+?Ala219ProPro205Gly?+?Ser222AspLeu221Val?+?Thr224GlnTrp208Ile?+?Pro214SerTrp208Asp?+?Thr212ProAla204Thr?+?Gly223GlnThr217Gln?+?Tyr218IleTyr213His?+?Ser216AspThr212Ser?+?Thr215AspThr217Asn?+?Leu221AsnPro214Asp?+?Thr217ProSer207Glu?+?Ala219HisThr217Asp?+?Tyr218HisTrp208Ala?+?Thr217SerPro205Gln?+?Ser220AspIle209Gly?+?Ser216GluTyr218Ser?+?Ser220GluThr215Asn?+?Ser216GluThr215Gly?+?Tyr218GlnThr217Ser?+?Leu221AlaAla219Pro?+?Leu221HisPro205Gln?+?Leu221MetTyr213Met?+?Leu221IleTrp208Asn?+?Thr212SerSer207Glu?+?Thr224GlyPro205Ser?+?Leu221CysAla204Gly?+?Tyr210ValTrp208Phe?+?Ser222AspIle209Thr?+?Ser222GluLeu221Ile?+?Ser222GluTyr213Pro?+?Thr217GluIle209Thr?+?Ser216GluTyr210Cys?+?Ser222AspLeu221Glu?+?Thr224SerTyr213Ala?+?Thr217ProTrp208Cys?+?Thr215GluAla204Ser?+?Thr217SerIle209His?+?Gly223SerAla204Asn?+?Trp208Tyr
43Pro205Gln?+?Ser207GluAla204Asn?+?Trp208MetTyr210Pro?+?Leu221AspTyr210Gln?+?Thr215SerAla204Pro?+?Ser216GluAla204Gly?+?Ser222AspSer216Asp?+?Leu221MetTyr210Ile?+?Ala219AsnPro214Glu?+?Thr224SerPro205Gln?+?Thr215SerAla204Gly?+?Pro205AsnTyr210Asp?+?Tyr218ValTrp208Ser?+?Thr215GlySer222Glu?+?Thr224SerTrp208Gln?+?Ser216AspSer207Asp?+?Gly223SerPro205Gly?+?Tyr210CysThr212Gly?+?Thr224AspSer220Glu?+?Gly223ProGly206Pro?+?Tyr210MetTyr210Ser?+?Ser222AspSer207Glu?+?Pro214GlnPro205Gly?+?Gly223AsnTyr213Ser?+?Pro214AspPro214Gln?+?Ser220AspAla204Thr?+?Ser222GluAla219Asn?+?Leu221AspGly206Ser?+?Thr215ProThr212Asn?+?Tyr218ValThr217Pro?+?Gly223AspGly206Pro?+?Tyr218AsnGly206Gln?+?Thr217AspTyr210Ala?+?Ser220AspPro214Asp?+?Tyr218ValLeu221His?+?Gly223AspPro214Gln?+?Gly223AspIle209Pro?+?Ser216AspIle209Thr?+?Gly223AspPro214Asn?+?Ala219AspTyr218Cys?+?Ser220GluSer207Glu?+?Tyr218AsnTyr218Gly?+?Leu221GlnIle209Thr?+?Tyr218ValPro214Glu?+?Gly223SerTyr213Met?+?Ala219ThrSer222Glu?+?Thr224AsnTrp208Asp?+?Ile209MetThr212Gln?+?Pro214GlnSer207Asp?+?Tyr213LeuThr212Gln?+?Gly223ProTyr210Leu?+?Ser216GluSer216Asp?+?Ala219ThrTyr213Gln?+?Thr217AspGly206Pro?+?Ser222GluAla204Thr?+?Ser220AspAla219Thr?+?Thr224ProTrp208Ile?+?Ala219GluIle209Gly?+?Thr215SerGly206Gln?+?Tyr210GluPro214Gln?+?Ser220GluSer207Glu?+?Thr217AsnAla204Pro?+?Gly223AspIle209Cys?+?Ser222AspPro214Gly?+?Gly223ProIle209Met?+?Thr224ProPro214Glu?+?Thr217SerPro205Ser?+?Ser207AspTyr210Thr?+?Thr212GlnGly206Gln?+?Tyr218ProTyr218Val?+?Ser222GluLeu221Asn?+?Gly223GluPro205Gln?+?Tyr218ValPro205Gln?+?Thr217AsnTrp208His?+?Ile209AlaPro205Ser?+?Gly223GlnPro214Ser?+?Thr217GlyTyr218His?+?Ser222AspThr212Gln?+?Gly223SerThr215Glu?+?Ala219ThrTyr213Gly?+?Tyr218AspThr212Gln?+?Tyr213GlnTyr210Ile?+?Thr215AspAla204Asn?+?Gly223ProSer207Glu?+?Ile209AsnThr215Gln?+?Ala219AspSer220Asp?+?Gly223ProPro205Ser?+?Tyr213AlaTrp208Gly?+?Ser222GluThr215Glu?+?Tyr218AlaAla204Gln?+?Ala219GlnPro205Asn?+?Tyr213ThrTyr218Thr?+?Thr224GlnSer222Asp?+?Thr224SerAla204Pro?+?Tyr213CysGly206Gln?+?Leu221GlySer216Glu?+?Thr224SerSer207Asp?+?Ala219AsnTrp208Leu?+?Ile209HisPro205Ser?+?Tyr213ValThr212Gly?+?Thr215Asp
Table 24
Ring 6 - three mutant Gly206Ser + Thr212Ser + Ala219GluAla204Asn + Thr212Ser + Ser216GluPro205Gln + Leu221Glu + Gly223AsnTrp208Thr + Ile209Cys + Thr224AspIle209Met + Thr212Gln + Ser220AspTyr210Gly + Tyr213Gly + Thr224GlySer207Glu + Tyr210Ser + Gly223AsnTyr213Gly + Ser216Asp + Thr217SerPro205Asn + Ser216Glu + Thr224AsnThr215Glu + Ala219Gln + Leu221ThrAla204Asn + Thr217Asn + Tyr218GluThr212Ser + Thr217Gly + Thr224GlnAla204Ser + Tyr218His + Ala219GlnPro205Ser + Tyr213Ser + Leu221AsnAla204Ser + Gly206Ser + Ala219SerAla204Gly + Trp208Gln + Ser216AspSer207Glu + Tyr218Gln + Leu221MetAla204Gly + Thr215Pro + Gly223GlnIle209Gln + Tyr218Ala + Ala219ProAla204Asn + Trp208Met + Ser222GluTrp208Met + Ala219Pro + Ser222AspPro205Gly + Leu221Val + Thr224GlnAla204Thr + Thr212Pro + Gly223GlnGly206Gln + Ile209Gln + Thr212GlnGly206Pro + Ser220Glu + Leu221SerGly206Gln + Tyr210Gly + Ser222AspAla204Gly + Tyr213Thr + Pro214GlnAla204His + Thr212Gln + Thr224GlnGly206Gln + Pro214Asp + Tyr218SerThr212Asn + Ser216Asp + Thr217SerSer207Asp + Tyr213Ile + Thr224ProPro205Gln + Tyr213Met + Leu221HisTrp208Asn + Thr212Ser + Gly223AspSer207Glu + Leu221Gly + Thr224GlyPro205Ser + Tyr210Val + Leu221CysPro205Gly + Ile209His + Tyr213ThrIle209Pro + Tyr210Asn + Ser220AspPro205Gly + Thr212Pro + Thr224GlyTrp208Cys + Thr217Asp + Ala219AsnPro205Gly + Leu221Cys + Gly223ProAla204His + Ser216Glu + Leu221SerThr217Asp + Gly223Ser + Thr224GlyPro205Gln + Trp208Gln + Ile209AlaThr212Gly + Thr217Gly + Leu221HisGly206Asn + Thr212Gly + Tyr213GlyGly206Asn + Ser207Glu + Thr212SerThr212Gln + Leu221Glu + Gly223SerTyr210His + Thr215Asp + Thr224ProPro214Gln + Thr215Pro + Ser216GluPro205Gly + Tyr213Val + Gly223AspTrp208Phe + Thr215Asn + Thr224GlyTyr213Met + Ala219Pro + Ser220GluTrp208Phe + Ile209Ser + Tyr213GlnGly206Ser + Ser216Glu + Tyr218ProAla204Gln + Tyr210His + Thr224GluPro205Ser + Thr212Pro + Ala219SerPro205Gln + Tyr210Met + Thr217ProAla204Gly + Ile209His + Ser216GluThr212Asn + Thr217Ser + Thr224AsnGly206Pro + Tyr210Gly + Gly223GlnPro205Gln + Thr217Asp + Ala219ThrPro205Ser + Ile209Met + Ser216AspThr215Asn + Ser216Glu + Thr224SerPro205Gln + Leu22lThr + Ser222GluTyr210Cys + Ala219Asn + Leu221ThrAla204Ser + Gly206Ser + Ala219GlnIle209Pro + Ser216Asp + Leu221CysTrp208Thr + Tyr210Val + Thr212SerThr212Gly + Pro214Asp + Gly223GlnPro214Gln + Thr215Ser + Thr224GluThr212Ser + Pro214Gln + Leu221HisTrp208Gly + Ser220Glu + Gly223SerPro205Ser + Ser220Asp + Leu221ThrGly206Asn + Thr215Pro + Leu221AlaTyr213Leu + Leu221His + Gly223AspSer207Asp + Thr212Gly + Tyr218CysGly206Gln + Ile209Val + Ala219ThrTrp208Ile + Tyr218Ile + Gly223AsnAla204His + Ile209Gly + Ser216AspTrp208Leu + Thr212Gly + Ala219SerThr212Gln + Pro214Glu + Ala219ThrPro205Gln + Ser207Asp + Thr212ProPro205Ser + Tyr210Pro + Tyr218IleLeu221Ala + Gly223Asn + Thr224GluAla204Thr + Gly206Gln + Ser207AspSer216Glu + Ala219Gln + Gly223GlnPro205Gly + Trp208Leu + Leu221GlnThr217Gln + Gly223Gln + Thr224GluThr212Gly + Thr217Ser + Tyr218AlaGly206Asn + Gly223Asp + Thr224AsnAla204Gly + Tyr210Cys + Tyr213ThrGly206Ser + Thr212Asn + Thr215GlyAla204Asn + Thr212Asn + Ser216GluGly206Gln + Tyr218Cys + Gly223GluAla204Ser + Pro205Ser + Gly206AsnIle209Gly + Leu221Val + Thr224ProGly206Asn + Trp208His + Thr217GlyGly206Ser + Trp208Leu + Ser222AspPro205Gly + Thr212Gln + Ser222AspAla204Thr + Tyr213Gln + Thr224ProThr212Ser + Thr217Ser + Gly223AspPro205Ser + Tyr213Ile + Ser222GluIle209Pro + Tyr210Asp + Ala219ProGly206Gln + Thr215Pro + Ser220GluTrp208Cys + Tyr210Leu + Thr215GlyTrp208Tyr + Thr212Gln + Ser222GluGly206Asn + Ser222Asp + Gly223AsnPro205Gly + Gly206Asn + Leu221CysPro205Gln + Tyr213Ile + Ser216GluAla204His + Tyr210His + Ser220AspAla204Thr + Thr212Asn + Ala219AspSer207Glu + Tyr210Ala + Thr212GlyTyr210His + Thr217Gly + Leu221MetAla204Thr + Ile209Met + Ser222GluTrp208Pro + Ala219Pro + Ser222AspAla204His + Ile209Ser + Ser220GluPro214Ser + Leu221Glu + Gly223GlnGly206Pro + Leu221Met + Gly223AspAla204His + Tyr213Thr + Ser222AspTyr213Ala + Leu221Met + Ser222AspTrp208Leu + Thr212Ser + Pro214AspTyr213Ile + Ser216Glu + Thr217ProPro205Gln + Pro214Gln + Thr224GlyTyr213Cys + Thr217Gly + Ser220GluGly206Asn + Thr212Gly + Tyr218ProGly206Pro + Ser216Glu + Gly223ProThr212Gln + Thr215Gly + Ser222GluAla204Pro + Thr217Asp + Thr224SerPro205Ser + Thr212Pro + Ala219AspIle209Cys + Pro214Ser + Thr215AspIle209Cys + Ser220Asp + Gly223GlnThr217Gly + Ser220Asp + Leu221GlnAla204His + Pro205Asn + Trp208GluAla204Gln + Thr212Ser + Thr215AspPro214Asn + Ser220Glu + Leu221GlyIle209Gly + Thr215Asn + Ala219ProSer207Glu + Thr217Gln + Thr224SerAla204Gly + Thr215Asn + Gly223ProIle209Ser + Tyr213Ile + Leu221MetTyr210Thr + Pro214Ser + Ser222AspTyr210Leu + Thr212Ser + Leu221AsnGly206Asn + Pro214Asp + Tyr218MetGly206Asn + Pro214Gln + Ala219AsnSer207Glu + Pro214Ser + Ala219HisAla204Asn + Trp208Ala + Ile209GlnThr217Glu + Tyr218Leu + Gly223AsnTrp208Pro + Pro214Gly + Leu221AlaGly206Pro + Thr215Ser + Leu221CysAla204Ser + Ile209Val + Thr224AspTrp208Ile + Tyr210Pro + Thr224AspThr212Gln + Thr215Asn + Thr217AspTyr210Ser + Tyr213Cys + Thr217AsnThr212Gln + Ser222Asp + Gly223GlnTyr210Asn + Thr217Glu + Tyr218MetPro214Asn + Ala219Gln + Ser220GluPro205Ser + Trp208Met + Leu221AspAla204Asn + Tyr210Cys + Tyr213AsnTyr218Leu + Leu221His + Ser222GluAla204His + Tyr218Ser + Ser222AspGly206Pro + Tyr213Asn + Pro214AsnGly206Pro + Thr215Gln + Tyr218SerAla204Pro + Ile209His + Leu221ThrGly206Gln + Thr212Gly + Gly223GluThr215Gly + Tyr218Ala + Thr224ProPro205Gln + Tyr213Gly + Gly223GluAla204Gly + Tyr213Asn + Leu221ThrTrp208Gly + Ile209His + Thr215SerAla204His + Ser207Glu + Tyr213CysTrp208His + Tyr210His + Ser222AspPro205Gly + Tyr210Asp + Leu221GlnPro205Asn + Tyr210Ala + Pro214SerThr212Pro + Thr215Gln + Thr224AspAla204Thr + Tyr213Val + Pro214GluAla204Gly + Tyr210Pro + Pro214GluPro205Gly + Trp208His + Tyr218GlyGly206Ser + Ala219Gln + Gly223SerTyr213Thr + Tyr218Cys + Ser220GluThr215Pro + Ser216Glu + Leu221AsnPro205Gly + Thr212Asn + Thr224AspPro205Gly + Ser207Asp + Thr212Ser...
Table 25
ring 6-four sudden change variant Gly206Asn, +, Thr215Gln, +, Tyr218Ile, +, Leu221IleTyr210Gly, +, Thr212Gln, +, Tyr213Gly, +, Thr224GlyPro205Gly, +, Gly206Pro, +, Trp208Asn, +, Thr224SerIle209Thr, +, Pro214Asp, +, Thr217Asn, +, Tyr218CysAla204Ser, +, Tyr218His, +, Ala219Gln, +, Leu221AsnAla204Ser, +, Pro205Ser, +, Tyr213Ser, +, Ala219SerAla204Gly, +, Thr212Gln, +, Ser216Asp, +, Gly223SerSer207Glu, +, Thr215Pro, +, Tyr218Gln, +, Leu221MetAla204Gly, +, Ser216Asp, +, Ala219His, +, Gly223GlnIle209Gln, +, Tyr210Asp, +, Tyr218Ala, +, Ala219ProTrp208Met, +, Tyr218Leu, +, Ala219Pro, +, Ser222GluPro205Gly, +, Leu221Val, +, Ser222Asp, +, Thr224GlnAla204Thr, +, Thr212Pro, +, Ser222Glu, +, Gly223GlnGly206Gln, +, Ile209Gln, +, Thr212Gln, +, Leu221HisAla204Ser, +, Gly206Pro, +, Ser220Asp, +, Leu221SerAla204Gly, +, Thr212Gln, +, Tyr213Thr, +, Thr224GlnTyr210Ala, +, Pro214Ser, +, Tyr218Val, +, Ser222AspAla204Gln, +, Pro205Ser, +, Gly206Ser, +, Ser222GluTrp208Cys, +, Pro214Gln, +, Ala219Thr, +, Thr224AspAla204Gly, +, Gly206Ser, +, Tyr210Asp, +, Leu221GlyAla204Gln, +, Gly206Asn, +, Tyr210Gln, +, Ala219AspPro205Ser, +, Gly206Pro, +, Ile209Val, +, Tyr213ProGly206Pro, +, Pro214Glu, +, Thr215Pro, +, Leu221MetSer207Asp, +, Trp208Met, +, Tyr218Val, +, Leu221ProTyr210Gly, +, Thr212Pro, +, Pro214Gly, +, Ser222AspGly206Pro, +, Thr212Gln, +, Thr217Ser, +, Ser222AspAla204Pro, +, Trp208Met, +, Ile209Val, +, Ser216GluTrp208Ser, +, Tyr218His, +, Ala219His, +, Gly223Pro
49Ala204Gln?+?Trp208Ala?+?Tyr210Asn?+?Ser222GluGly206Gln?+?Ser220Asp?+?Leu221Ala?+?Thr224SerIle209Gln?+?Thr212Ser?+?Ala219Gln?+?Ser220GluPro205Asn?+?Thr212Gly?+?Tyr218Ala?+?Ser222GluPro205Gln?+?Trp208Cys?+?Tyr213Cys?+?Pro214AspPro205Gly?+?Thr215Gln?+?Thr217Pro?+?Gly223SerAla204His?+?Gly206Pro?+?Ser216Glu?+?Leu221SerSer207Asp?+?Leu221Gly?+?Gly223Gln?+?Thr224AsnTyr210His?+?Thr212Ser?+?Leu221Glu?+?Gly223SerPro205Gly?+?Thr215Asn?+?Gly223Asp?+?Thr224GlyTrp208Phe?+?Tyr213Met?+?Thr215Pro?+?Ser220GluGly206Ser?+?Trp208Phe?+?Ile209Ser?+?Tyr213GlnAla204Gln?+?Pro205Ser?+?Thr212Pro?+?Ala219SerAla204Gly?+?Tyr210Met?+?Ser216Glu?+?Thr217ProGly206Pro?+?Thr212Asn?+?Thr217Gln?+?Thr224AsnPro205Ser?+?Ile209Met?+?Thr215Asn?+?Thr224SerTyr210Thr?+?Thr212Pro?+?Tyr218Asn?+?Ser220GluTrp208Thr?+?Tyr210Val?+?Thr212Ser?+?Leu221CysThr212Gly?+?Pro214Asp?+?Thr215Ser?+?Gly223GlnSer207Glu?+?Thr212Ser?+?Pro214Gln?+?Leu221ProPro205Asn?+?Gly206Gln?+?Ser207Asp?+?Leu221ThrPro205Ser?+?Thr215Pro?+?Ser220Asp?+?Leu221CysGly206Asn?+?Tyr213Leu?+?Leu221Ala?+?Gly223AspSer207Asp?+?Thr212Gly?+?Pro214Asn?+?Thr224AsnAla204Pro?+?Ser207Glu?+?Ile209Val?+?Ala219ThrGly206Gln?+?Trp208Ile?+?Tyr218Ile?+?Gly223AsnAla204His?+?Trp208Leu?+?Ile209Gly?+?Ser216AspAla204Gln?+?Thr212Gly?+?Pro214Glu?+?Ala219SerAla204Asn?+?Pro205Gln?+?Ser207Asp?+?Thr212ProPro205Gly?+?Trp208Leu?+?Ser216Glu?+?Ala219GlnTrp208Tyr?+?Thr217Gln?+?Leu221Gln?+?Thr224GluThr212Gly?+?Thr217Ser?+?Tyr218Ala?+?Gly223AspAla204Gly?+?Gly206Asn?+?Thr215Asn?+?Gly223AspGly206Ser?+?Tyr210Cys?+?Tyr213Thr?+?Thr215GlyAla204Gln?+?Pro205Ser?+?Gly206Asn?+?Ala219AspAla204Ser?+?Ile209Gly?+?Leu221Val?+?Thr224ProGly206Asn?+?Ser207Glu?+?Trp208His?+?Thr217GlyGly206Ser?+?Trp208Pro?+?Ala219Thr?+?Ser222AspAla204Thr?+?Tyr213Gln?+?Thr217Ser?+?Thr224ProPro205Ser?+?Thr212Ser?+?Tyr213Ile?+?Gly223AspGly206Gln?+?Ile209Asn?+?Thr215Pro?+?Ser220GluTrp208Cys?+?Thr212Gln?+?Thr215Gly?+?Ser222GluGly206Asn?+?Trp208Tyr?+?Ser222Glu?+?Gly223AsnPro205Gly?+?Gly206Asn?+?Leu221Cys?+?Ser222AspPro205Gln?+?Tyr210His?+?Tyr213Ile?+?Ser220AspAla204His?+?Trp208Asn?+?Thr212Asn?+?Ala219AspAla204His?+?Gly206Pro?+?Leu221Met?+?Gly223AspAla204Ser?+?Tyr213Thr?+?Leu221Met?+?Ser222AspTyr213Ile?+?Pro214Gln?+?Ser216Glu?+?Thr217ProPro205Gln?+?Tyr213Cys?+?Ser220Glu?+?Thr224GlyGly206Asn?+?Tyr213Asn?+?Tyr218Pro?+?Ser220GluPro205Ser?+?Gly206Pro?+?Tyr218Asp?+?Gly223ProAla204Pro?+?Pro205Ser?+?Thr217Asp?+?Thr224SerPro205Asn?+?Trp208Ile?+?Thr212Gln?+?Thr217GlyIle209Cys?+?Pro214Ser?+?Ser220Asp?+?Gly223GlnAla204His?+?Pro205Asn?+?Trp208Glu?+?Tyr210HisIle209Gly?+?Thr215Asn?+?Thr217Asn?+?Ala219ProPro205Gly?+?Pro214Asn?+?Tyr218Ile?+?Ser222AspAla204Ser?+?Pro205Ser?+?Thr212Asn?+?Tyr213IlePro205Gln?+?Ser207Glu?+?Tyr210Pro?+?Thr215SerPro205Gln?+?Ser207Glu?+?Thr212Gln?+?Tyr213SerAla204Ser?+?Ile209Asn?+?Tyr213Cys?+?Ser216AspTrp208Ala?+?Ile209Gln?+?Thr217Glu?+?Gly223AsnTrp208Pro?+?Pro214Gly?+?Tyr218Leu?+?Leu221AlaGly206Pro?+?Thr215Ser?+?Ser216Glu?+?Leu221CysAla204Ser?+?Trp208Ile?+?Ile209Val?+?Thr224AspTyr210Pro?+?Thr212Gln?+?Thr215Asn?+?Thr217AspTyr210Ser?+?Tyr213Cys?+?Pro214Asn?+?Thr217AsnThr212Gln?+?Tyr218Met?+?Ser222Asp?+?Gly223GlnPro205Ser?+?Trp208Met?+?Ala219Gln?+?Leu221AspAla204Asn?+?Tyr210Cys?+?Tyr213Asn?+?Tyr218LeuAla204His?+?Pro205Gly?+?Tyr218Ser?+?Ser222AspGly206Pro?+?Tyr213Asn?+?Pro214Asn?+?Tyr218SerAla204Pro?+?Ile209His?+?Thr215Gln?+?Leu221ThrAla204Asn?+?Gly206Gln?+?Thr212Gly?+?Gly223GluThr215Gly?+?Tyr218Ala?+?Gly223Glu?+?Thr224ProPro205Gln?+?Tyr213Gly?+?Ser220Asp?+?Leu221ThrPro205Gly?+?Trp208His?+?Tyr210His?+?Leu221GlnTyr210Leu?+?Thr212Pro?+?Tyr218Gln?+?Ala219GluGly206Gln?+?Thr212Gln?+?Tyr218His?+?Gly223AspTrp208Ile?+?Tyr213His?+?Thr215Ser?+?Ser222GluTrp208Val?+?Pro214Asn?+?Thr215Gly?+?Leu221AspPro205Asn?+?Tyr213Met?+?Pro214Ser?+?Thr224SerPro205Gly?+?Trp208Met?+?Ile209Leu?+?Tyr213MetPro205Gly?+?Thr217Glu?+?Tyr218Leu?+?Ala219HisTrp208Val?+?Tyr213Gly?+?Ser216Asp?+?Leu221ThrTyr210Gln?+?Thr212Pro?+?Tyr218Gly?+?Gly223GluPro205Gly?+?Trp208Asp?+?Ile209His?+?Tyr210AlaTrp208Ala?+?Ile209Leu?+?Tyr210Glu?+?Tyr213CysGly206Asn?+?Trp208Leu?+?Tyr213Val?+?Ser216AspAla204Pro?+?Pro205Gly?+?Thr217Glu?+?Leu221AlaTrp208Asn?+?Thr212Asn?+?Tyr213His?+?Ser216GluAla204His?+?Thr212Gly?+?Ala219Gln?+?Leu221ThrGly206Gln?+?Thr212Pro?+?Tyr213Met?+?Thr224ProTrp208Thr?+?Ile209Gln?+?Tyr213Ser?+?Ser222AspAla204Asn?+?Ile209Asn?+?Tyr213Pro?+?Leu221ProPro205Gly?+?Tyr210His?+?Tyr218Ile?+?Leu221AsnAla204Pro?+?Tyr210Cys?+?Pro214Gln?+?Thr215ProPro205Ser?+?Tyr213Ser?+?Ser216Asp?+?Thr217GlyPro205Asn?+?Trp208Ser?+?Ala219Glu?+?Ser220AspTyr210Ala?+?Tyr218Met?+?Ala219Glu?+?Ser220AspAla204Gly?+?Pro205Gln?+?Pro214Asp?+?Thr215AspTyr210Ser?+?Thr215Asn?+?Ser222Glu?+?Gly223GluGly206Pro?+?Tyr213Val?+?Ser222Glu?+?Gly223AspPro214Ser?+?Leu221Glu?+?Ser222Asp?+?Gly223GlnPro205Gln?+?Ser216Asp?+?Thr217Glu?+?Ala219ThrTrp208Leu?+?Thr212Gln?+?Ser220Glu?+?Leu221GluGly206Gln?+?Ser220Asp?+?Leu221Asp?+?Gly223AsnThr217Asp?+?Tyr218Asp?+?Gly223Ser?+?Thr224GlyPro205Gln?+?Ile209Ala?+?Thr217Glu?+?Tyr218GluPro214Gln?+?Thr215Asp?+?Ser216Glu?+?Thr224ProAla204His?+?Ser207Glu?+?Tyr213Cys?+?Ser222AspPro205Gly?+?Ser207Glu?+?Thr212Gln?+?Ser222AspSer207Glu?+?Tyr210Ser?+?Tyr218Leu?+?Ser222GluSer207Glu?+?Tyr218Cys?+?Ser222Glu?+?Thr224ProPro205Ser?+?Trp208Glu?+?Leu221Glu?+?Ser222GluTrp208Glu?+?Ile209Asn?+?Thr217Gly?+?Ser222GluSer216Glu?+?Thr217Asp?+?Tyr218Glu?+?Thr224GlyTrp208Asp?+?Tyr218Leu?+?Ala219Thr?+?Leu221GluAla204His?+?Thr212Gly?+?Thr215Glu?+?Thr217GluPro214Asp?+?Ser216Asp?+?Ala219His?+?Gly223AsnTyr210Pro?+?Pro214Asp?+?Ser216Glu?+?Tyr218IlePro205Gln?+?Tyr210Leu?+?Pro214Glu?+?Thr217AspAla204Ser?+?Ser207Glu?+?Pro214Ser?+?Gly223AspSer207Asp?+?Thr212Pro?+?Thr217Gly?+?Gly223AspSer207Glu?+?Pro214Asn?+?Ser220Glu?+?Ser222AspPro205Ser?+?Thr217Pro?+?Ala219Glu?+?Leu221GluTrp208Gln?+?Tyr210Glu?+?Thr212Asn?+?Leu221GluTrp208Gln?+?Thr215Pro?+?Ser220Glu?+?Ser222GluGly206Pro?+?Thr217Gly?+?Ser220Asp?+?Ser222GluGly206Gln?+?Tyr210Gly?+?Ser220Glu?+?Ser222AspSer207Glu?+?Thr212Asn?+?Tyr218Pro?+?Leu221AspAla204Asn?+?Ser207Glu?+?Trp208His?+?Leu221AspTyr213Ile?+?Tyr218Leu?+?Ser222Asp?+?Thr224GluGly206Gln?+?Tyr210Met?+?Ser222Asp?+?Thr224GluIle209Ser?+?Tyr210His?+?Ser222Glu?+?Thr224AspAla204Ser?+?Tyr218Asp?+?Ala219Pro?+?Ser220GluGly206Gln?+?Thr217Ser?+?Tyr218Glu?+?Ser220GluPro214Asp?+?Tyr218Asp?+?Gly223Ser?+?Thr224GlyGly206Gln?+?Tyr210Gly?+?Pro214Glu?+?Tyr218GluTrp208Asp?+?Thr217Gln?+?Ser220Asp?+?Gly223AspSer207Glu?+?Tyr210Ala?+?Thr215Asn?+?Ser220AspSer207Glu?+?Thr217Gly?+?Ser220Asp?+?Leu221GlnSer207Glu?+?Thr217Gly?+?Tyr218Asn?+?Ser220AspPro205Asn?+?Ser207Asp?+?Thr212Gly?+?Ser220AspSer207Glu?+?Thr212Asn?+?Ala219Gly?+?Ser220AspGly206Pro?+?Ser207Glu?+?Trp208Asp?+?Thr224AspSer207Asp?+?Trp208Thr?+?Tyr218Gln?+?Thr224GluAla204Thr?+?Ser207Asp?+?Leu221Ala?+?Thr224GluSer207Asp?+?Ala219Glu?+?Ser220Asp?+?Gly223SerSer207Glu?+?Tyr210Glu?+?Thr215Gln?+?Thr224AsnAla204Gln?+?Tyr210Glu?+?Thr212Asn?+?Ser222Asp
Table 26
Ring 6-five replacement varient Gly206Asn+Tyr210Gly+Thr212Gln+Tyr218Ile+
Thr224GlyAla204Asn?+?Pro205Gly?+?Trp208Glu?+?Thr215Asn?+
Gly223ProPro205Gln?+?Gly206Pro?+?Trp208Asn?+?Thr212Gln?+
Thr224SerAla204Ser?+?Pro205Ser?+?Tyr213Ser?+?Thr215Ser?+
Ala219GlyAla204Gly?+?Gly206Gln?+?Thr212Pro?+?Ser220Asp?+
Leu221SerPro214Ser?+?Thr215Gln?+?Tyr218Val?+?Ser222Asp?+
Thr224AsnAla204Pro?+?Ser207Asp?+?Tyr210Cys?+?Thr212Pro?+
Thr215ProGly206Asn?+?Pro214Gln?+?Ala219Gly?+?Gly223Asn?+
Thr224AspAla204Gln?+?Pro205Ser?+?Gly206Ser?+?Tyr210Gln?+
Ala219AspGly206Pro?+?Ser207Asp?+?Trp208Met?+?Thr215Pro?+
Leu221ProAla204Asn?+?Pro205Gln?+?Tyr210Cys?+?Thr212Asn?+
Leu221SerAla204Asn?+?Gly206Gln?+?Trp208Thr?+?Ile209Ser?+
Ser222AspPro205Gln?+?Tyr213Leu?+?Thr217Glu?+?Tyr218Met?+
Leu221GlnAla204Pro?+?Trp208Met?+?Ile209Val?+?Tyr210Leu?+
Ser216GluTrp208Ser?+?Ile209Ser?+?Tyr218His?+?Ala219His?+
Gly223ProTrp208Pro?+?Ile209Thr?+?Thr212Gly?+?Thr215Gly?+
Thr224GluIle209Val?+?Pro214Ser?+?Ser216Asp?+?Tyr218Met?+
Leu221MetGly206Gln?+?Ile209Gln?+?Ser220Asp?+?Leu221Gly?+
Thr224SerPro205Gln?+?Trp208Cys?+?Thr212Asn?+?Tyr213Cys?+
Pro214AspPro205Gln?+?Trp208Gln?+?Thr217Asp?+?Gly223Ser?+
Thr224GlySer207Glu?+?Thr212Ser?+?Thr217Gly?+?Tyr218Gln?+
Leu221HisTyr210His?+?Thr212Ser?+?Leu221Glu?+?Gly223Ser?+
Thr224ProTrp208Phe?+?Tyr213Met?+?Thr215Pro?+?Ser220Glu?+
Thr224GlyGly206Ser?+?Trp208Phe?+??Ile209Ser?+?Tyr213Cys?+
Ser216GluAla204Gln?+?Pro205Ser?+?Tyr210His?+?Tyr218Pro?+
Thr224GluPro205Gln?+?Gly206Gln?+?Leu221His?+?Ser222Asp?+
Gly223GlnAla204Gly?+?Ile209His?+?Tyr210Met?+?Ser216Glu?+
Thr217ProGly206Pro?+?Ile209Ala?+?Tyr210Gly?+?Leu221Asp?+
Gly223GlnGly206Asn?+?Tyr210Met?+?Thr215Glu?+?Gly223Asn?+
Thr224GlyGly206Gln?+?Ile209Pro?+?Ser216Asp?+?Leu221Cys?+
Gly223ProTrp208Thr?+?Tyr210Val?+?Thr212Ser?+?Pro214Asp?+
Gly223GlnThr212Gly?+?Pro214Gln?+?Thr215Ser?+?Leu221Gly?+
Thr224GluAla204Thr?+?Thr212Ser?+?Thr217Ser?+?Gly223Asp?+
Thr224ProPro205Ser?+?Ile209Pro?+?Tyr213Ile?+?Ala219Pro?+
Ser222GluTrp208Gly?+?Thr212Gln?+?Tyr218Gly?+?Ser222Glu?+
Gly223SerGly206Pro?+?Ile209Pro?+?Tyr213Ser?+?Thr217Gly?+
Tyr218ValPro205Gln?+?Tyr213Cys?+?Pro214Gln?+?Ser220Glu?+
Thr224GlyGly206Asn?+?Thr212Gly?+?Tyr213Asn?+?Tyr218Pro?+
Ser220GluAla204Pro?+?Pro205Ser?+?Thr212Gln?+?Thr217Asp?+
Thr224SerPro205Asn?+?Trp208Ile?+?Thr212Gln?+?Pro214Ser?+
Thr217GlyIle209Cys?+?Thr217Gly?+?Ser220Asp?+?Leu221Gln?+
Gly223GlnIle209Thr?+?Thr215Gly?+?Ser216Glu?+?Tyr218Leu?+
Ala219ProIle209Met?+?Pro214Gly?+?Thr217Gly?+?Tyr218Cys?+
Leu221MetPro205Gly?+?Pro214Asn?+?Tyr218Ile?+?Ala219Gly?+
Ser222AspTyr210Thr?+?Thr212Ser?+?Pro214Ser?+?Leu221Asn?+
Ser222AspGly206Asn?+?Tyr210Ile?+?Pro214Gln?+?Ala219Asn?+
Leu221ValPro205Asn?+?Thr215Ser?+?Ala219Ser?+?Leu221Ala?+
Thr224AspGly206Pro?+?Pro214Asn?+?Thr215Gln?+?Tyr218Ser?+
Leu221ThrAla204Pro?+?Gly206Gln?+?Ile209His?+?Thr212Gly?+
Gly223GluPro205Gln?+?Tyr213Gly?+?Tyr218Ala?+?Gly223Glu?+
Thr224ProPro205Ser?+?Pro214Gly?+?Thr217Pro?+?Ala219Thr?+
Leu221GluAla204Pro?+?Pro205Asn?+?Ser207Asp?+?Tyr210Ala?+
Pro214SerGly206Ser?+?Tyr213Thr?+?Ala219Gln?+?Ser220Glu?+
Gly223SerPro205Gly?+?Thr212Asn?+?Thr215Pro?+?Ser216Glu?+
Leu221AsnSer207Glu?+?Ile209Ala?+?Thr212Asn?+?Thr215Gln?+
Tyr218MetTyr213His?+?Thr215Gln?+?Thr217Asn?+?Ala219Glu?+
Leu221SerGly206Gln?+?Tyr213Asn?+?Thr215Ser?+?Tyr218Ala?+
Leu221AlaTrp208Met?+?Tyr210Met?+?Tyr218Gln?+?Ser220Glu?+
Thr224SerAla204Thr?+?Pro205Ser?+?Ile209Leu?+?Thr217Asn?+
Thr224ProPro205Gly?+?Ile209Leu?+?Thr215Asn?+?Ser216Glu?+
Gly223SerIle209Ser?+?Tyr213Leu?+?Thr217Asp?+?Tyr218Asn?+
Ala219HisAla204Ser?+?Pro205Ser?+?Ser207Glu?+?Leu221Val?+
G1y223ProAla204His?+?Thr212Gly?+?Ala219Gln?+?Leu221Thr?+
Gly223GluPro205Ser?+?Gly206Gln?+?Thr212Pro?+?Gly223Pro?+
Thr224ProAla204Asn?+?Trp208Thr?+?Tyr213Pro?+?Leu221Pro?+
Ser222AspPro205Gly?+?Ile209Met?+?Tyr218Met?+?Leu221Val?+
Gly223AsnThr212Gly?+?Tyr218Ile?+?Ala219Asn?+?Ser220Glu?+
Thr224ProAla204Gln?+?Pro205Gln?+?Gly206Gln?+?Ile209Met?+
Ser216AspAla204Thr?+?Thr212Gly?+?Ala219Asn?+?Gly223Asp?+
Thr224AsnAla204Pro?+?Trp208His?+?Tyr213Leu?+?Thr217Ser?+
Ser222GluPro205Ser?+?Ser207Asp?+?Ile209Asn?+?Tyr213Met?+
Thr217GlnGly206Pro?+?Trp208Ser?+?Thr212Gly?+?Tyr213Cys?+
Gly223GluAla204Asn?+?Gly206Pro?+?Trp208Val?+?Pro214Asn?+
Tyr218GluIle209Gly?+?Tyr210Ala?+?Tyr218Pro?+?Gly223Ser?+
Thr224SerPro205Gln?+?Tyr213His?+?Tyr218Met?+?Ser220Glu?+
Leu221GlyAla204Asn?+?Tyr210Cys?+?Thr212Gln?+?Tyr218Leu?+
Ser222AspGly206Ser?+?Ile209Leu?+?Thr212Gly?+?Pro214Gln?+
Thr215GluSer207Asp?+?Pro214Ser?+?Thr215Asn?+?Thr217Asn?+
Leu221SerPro205Gly?+?Trp208Thr?+?Thr217Gly?+?Ser220Glu?+
Gly223SerGly206Ser?+?Trp208Glu?+?Tyr210Gln?+?Thr217Gln?+
Leu221ProGly206Gln?+?Ser207Glu?+?Thr212Asn?+?Pro214Ser?+
Leu221AlaAla204Ser?+?Trp208Leu?+?Ile209Asn?+?Thr215Asp?+
Thr224AsnGly206Ser?+?Ile209Pro?+?Thr217Ser?+?Ser220Glu?+
Gly223GlnPro205Gln?+?Trp208Pro?+?Thr212Pro?+?Pro214Glu?+
Ala219SerGly206Pro?+?Ser207Glu?+?Tyr210Met?+?Thr212Gly?+
Tyr213LeuAla204His?+?Tyr210Pro?+?Tyr213Ala?+?Thr217Glu?+
Thr224SerTrp208Cys?+?Ile209Met?+?Tyr210Ala?+?Tyr213Met?+
Ala219AsnTrp208Thr?+?Tyr210Ala?+?Tyr218Met?+?Ala219Glu?+
Ser220AspTrp208Asn?+?Ile209Pro?+?Ala219Asp?+?Ser220Asp?+
Gly223SerPro205Ser?+?Tyr213Thr?+?Pro214Asp?+?Thr215Asp?+
Tyr218ValIle209Ser?+?Tyr213Pro?+?Leu221Met?+?Ser222Asp?+
Gly223AspAla204Thr?+?Thr217Gln?+?Tyr218Ile?+?Ser222Glu?+
Gly223AspPro205Ser?+?Tyr210Ala?+?Thr215Asn?+?Ser222Glu?+
Gly223GluTyr210Pro?+?Thr212Pro?+?Leu221Asn?+?Ser222Asp?+
Gly223AspTrp208Pro?+?Ile209Pro?+?Tyr213Ile?+?Ser222Asp?+
Gly223AspGly206Gln?+?Tyr213Gly?+?Thr217Gly?+?Ser222Glu?+
Gly223GluTrp208Ser?+?Ile209Pro?+?Thr212Pro?+?Ser216Glu?+
Thr217AspGly206Asn?+?Tyr218Met?+?Ala219His?+?Ser220Glu?+
Leu221AspIle209Ala?+?Thr215Glu?+?Ser216Glu?+?Gly223Gln?+
Thr224AsnIle209Gly?+?Pro214Ser?+?Thr215Glu?+?Ser216Asp?+
Tyr218IleAla204Ser?+?Trp208Val?+?Ile209Ser?+?Thr215Glu?+
Ser216AspThr212Pro?+?Thr215Asp?+?Ser216Glu?+?Thr217Glu?+
Thr224SerAla204His?+?Ser207Glu?+?Trp208His?+?Tyr210His?+
Ser222AspSer207Glu?+?Tyr213Asn?+?Leu221Thr?+?Ser222Asp?+
Thr224GlyGly206Ser?+?Ser207Glu?+?Trp208Pro?+?Ala219Thr?+
Ser222AspPro205Gly?+?Ser207Glu?+?Thr212Gln?+?Tyr213Gln?+
Ser222AspPro205Ser?+?Ser207Glu?+?Tyr213His?+?Thr217Pro?+
Ser222GluGly206Pro?+?Ser207Asp?+?Tyr213Ile?+?Tyr218Asn?+
Ser222GluGly206Pro?+?Trp208Glu?+?Tyr210Cys?+?Pro214Gln?+
Ser220AspTyr210Glu?+?Tyr213Gly?+?Tyr218Leu?+?Ala219Asp?+
Thr224SerGly206Pro?+?Ser207Asp?+?Leu221Asp?+?Ser222Glu?+
Thr224GlnTyr213Ser?+?Pro214Ser?+?Thr215Glu?+?Thr217Asp?+
Tyr218AlaAla204Asn?+?Tyr210Gln?+?Thr212Asn?+?Pro214Glu?+
Ser216AspPro205Gln?+?Gly206Pro?+?Pro214Glu?+?Ser216Asp?+
Thr224SerSer207Asp?+?Thr212Pro?+?Thr215Gly?+?Thr217Gly?+
Gly223AspSer207Glu?+?Tyr210Val?+?Pro214Asn?+?Leu221Thr?+
Gly223GluSer207Asp?+?Ile209Thr?+?Tyr210Met?+?Thr212Pro?+
Gly223AspSer207Glu?+?Tyr210Ser?+?Tyr218Leu?+?Ser220Asp?+
Ser222GluSer207Asp?+?Thr217Gln?+?Ser220Asp?+?Ser222Asp?+
Thr224AsnTrp208Thr?+?Thr217Glu?+?Tyr218Ser?+?Ala219Glu?+
Leu221CysPro205Gly?+?Thr212Ser?+?Ala219Gln?+?Ser220Glu?+
Ser222GluGly206Pro?+?Trp208His?+?Tyr210Gly?+?Ser220Glu?+
Ser222AspAla204Gln?+?Gly206Ser?+?Trp208Gln?+?Ser220Glu?+
Ser222GluAla204Ser?+?Tyr213Thr?+?Ser220Asp?+?Leu221Met?+
Ser222AspThr212Gly?+?Thr215Asp?+?Ser216Asp?+?Thr217Gly?+
Tyr218AspAla204Asn?+?Tyr210Glu?+?Tyr213Ala?+?Ser220Glu?+
Ser222GluAla204His?+?Gly206Pro?+?Ser216Glu?+?Tyr218Asp?+
Leu221SerGly206Pro?+?Ile209Ser?+?Tyr210His?+?Ser222Glu?+
Thr224AspTrp208Met?+?Tyr218Leu?+?Ala219Pro?+?Ser222Glu?+
Thr224GluTrp208Val?+?Tyr210Leu?+?Thr212Asn?+?Tyr218Asp?+
Ser220GluAla204Ser?+?Tyr213Gln?+?Tyr218Asp?+?Ala219Pro?+
Ser220GluThr212Asn?+?Tyr213Gln?+?Thr217Ser?+?Tyr218Glu?+
Ser220GluPro214Ser?+?Leu221Glu?+?Ser222Asp?+?Gly223Ser?+
Thr224AspPro205Gly?+?Tyr210Cys?+?Ala219Asp?+?Ser220Glu?+
Ser222AspGly206Gln?+?Tyr210Gly?+?Pro214Glu?+?Thr217Pro?+
Tyr218GluTrp208Asp?+?Pro214Ser?+?Thr217Gln?+?Ser220Asp?+
Gly223AspSer207Glu?+?Tyr210Ala?+?Thr215Asn?+?Ser220Asp?+
Leu221AlaSer207Asp?+?Trp208Cys?+?Ile209Ala?+?Thr215Asn?+
Ser220GluSer207Asp?+?Tyr210Met?+?Tyr218Asn?+?Ser220Glu?+
Leu221CysSer207Glu?+?Tyr210Pro?+?Thr215Gln?+?Tyr218Cys?+
Ser220GluSer207Glu?+?Thr212Ser?+?Pro214Gln?+?Ser220Asp?+
Leu221ProPro205Asn?+?Ser207Asp?+?Thr215Pro?+?Ser220Asp?+
Leu221ThrTrp208Glu?+?Ile209Asn?+?Thr217Gly?+?Ala219Asp?+
Ser222GluPro205Asn?+?Ser207Glu?+?Tyr213Leu?+?Ser220Asp?+
Gly223GluAla204Ser?+?Pro205Gly?+?Ser207Asp?+?Thr212Ser?+
Thr224AspAla204Pro?+?Gly206Gln?+?Ser207Glu?+?Tyr218Asn?+
Thr224GluGly206Ser?+?Ser207Glu?+?Tyr210Met?+?Tyr213Cys?+
Thr224AspPro205Asn?+?Ser207Glu?+?Ile209Val?+?Tyr213Pro?+
Thr224GluSer207Asp?+?Ile209Val?+?Tyr213Ala?+?Gly223Gln?+
Thr224GluPro205Asn?+?Ser207Glu?+?Ala219Glu?+?Ser220Glu?+
Gly223GlnGly206Asn?+?Ser207Glu?+?Trp208Asp?+?Ala219Asp?+
Thr224ProAla204Gly?+?Gly206Ser?+?Ser207Asp?+?Tyr210Asp?+
Leu221GlyAla204Pro?+?Ser207Glu?+?Ile209Thr?+?Tyr210Glu?+
Tyr218LeuIle209Thr?+?Tyr213Gly?+?Ala219Asp?+?Ser222Glu?+
Gly223AspPro205Gln?+?Tyr213Gln?+?Tyr218Glu?+?Leu221Glu?+
Ser222AspGly206Gln?+?Ser207Glu?+?Thr212Asn?+?Ser220Glu?+
Thr224GluSer207Glu?+?Thr217Gly?+?Tyr218Asn?+?Ser220Asp?+
Thr224GluAla204Thr?+?Tyr210Cys?+?Ser220Glu?+?Leu221Ser?+
Gly223GluIle209Pro?+?Ser216Glu?+?Ala219Glu?+?Ser220Asp?+
Gly223AsnGly206Gln?+?Tyr210Met?+?Thr212Pro?+?Ala219Glu?+
Ser222AspPro205Asn?+?Tyr210Glu?+?Thr217Asp?+?Tyr218Ala?+
Thr224ProAla204Gly?+?Trp208Gln?+?Thr212Gln?+?Ser216Asp?+
Ala219GluAla204Asn?+?Trp208Ala?+?Ser216Asp?+?Ala219Glu?+
Thr224GlyAla204Asn?+?Tyr210Asp?+?Thr215Glu?+?Thr217Glu?+
Ala219GlyTrp208Leu?+?Ile209Gly?+?Thr215Asp?+?Thr217Glu?+
Ser220AspThr212Pro?+?Tyr213Leu?+?Ser216Glu?+?Tyr218Glu?+
Leu221GluThr217Asp?+?Ala219Glu?+?Leu221Asn?+?Ser222Glu?+
Thr224SerPro205Ser?+?Trp208Glu?+?Tyr218Glu?+?Leu221Gly?+
Ser222GluSer207Glu?+?Thr215Pro?+?Thr217Asp?+?Ser220Glu?+
Gly223ProThr217Asp?+?Ala219Asn?+?Leu221Glu?+?Ser222Glu?+
Gly223AsnTrp208Tyr?+?Ile209Asn?+?Thr217Glu?+?Leu221Glu?+
Ser222AspAla204Gly?+?Tyr210Glu?+?Pro214Glu?+?Ser216Glu?+
Thr217AsnPro214Asp?+?Thr215Gln?+?Ser216Glu?+?Ser220Glu?+
Leu221MetAla204Gln?+?Tyr210Glu?+?Thr212Asn?+?Thr217Glu?+
Ser222AspTrp208Leu?+?Ile209Val?+?Thr215Asp?+?Thr217Glu?+
Leu221GluGly206Pro?+?Ile209Val?+?Tyr213Pro?+?Thr215Asp?+
Ala219GluPro205Asn?+?Ser207Glu?+?Tyr218Asp?+?Ser222Asp?+
Thr224GlyGly206Ser?+?Tyr210Asp?+?Pro214Asp?+?Thr215Pro?+
Leu221AspTyr210Ser?+?Pro214Asp?+?Tyr218Cys?+?Ser220Glu?+
Ser222GluSer207Asp?+?Ile209Ser?+?Thr212Ser?+?Pro214Asp?+
Thr215Asp
Table 27
Ring 6 - six substituted variants
Gly206Asn + Tyr210Gly + Thr212Gln + Tyr213Gly +
Tyr218Ile + Thr224Gly
Pro205Asn + Gly206Ser + Tyr213Gly + Ser216Asp +
Thr217Ser + Thr224Asn
Ala204Ser + Pro205Ser + Tyr213Ser + Tyr218His +
Ala219Gln + Leu221Asn
Ser207Glu + Thr212Gln + Thr215Pro + Tyr218Gln +
Leu221Met + Gly223Gln
Pro205Ser + Ser207Asp + Tyr210Val + Tyr213Leu +
Leu221Gln + Thr224Gly
Ala204Ser + Trp208Cys + Ile209His + Thr215Glu +
Thr217Pro + Gly223Ser
Ala204Gly + Ile209Asn + Tyr210Ile + Ser216Asp +
Ala219Asn + Leu221Met
Ala204Gly + Pro205Gln + Pro214Glu + Thr215Ser +
Tyr218Asn + Thr224Ser
Gly206Asn + Trp208Cys + Thr212Gly + Tyr213Gly +
Ser216Asp + Leu221His
Trp208Pro + Ile209Gly + Thr215Ser + Ala219Thr +
Leu221Thr + Thr224Asp
Pro205Gly + Gly206Gln + Ile209Gly + Thr212Asn +
Pro214Asn + Ser220Glu
Pro205Gly + Trp208Leu + Thr217Gln + Leu221Gln +
Gly223Gln + Thr224Glu
Ala204Gly + Gly206Asn + Tyr210Cys + Tyr213Thr +
Gly223Asp + Thr224Asn
Gly206Asn + Trp208His + Ile209Gly + Thr217Gly +
Leu221Val + Thr224Pro
Ala204Thr + Thr212Gln + Tyr213Gln + Thr217Ser +
Ser222Asp + Thr224Pro
Trp208Gly + Thr212Gln + Tyr213Leu + Tyr218Gly +
Ser222Glu + Gly223Ser
Pro205Ser + Trp208Ser + Tyr213Asn + Tyr218Gln +
Ser222Asp + Thr224Gln
Ala204His + Pro205Gly + Ile209Asn + Tyr213Gln +
Thr215Ser + Thr217Ser
Ala204Thr + Gly206Asn + Trp208Leu + Thr215Ser +
Ser216Asp + Ala219His
Gly206Ser + Thr212Gln + Tyr213Val + Tyr218Cys +
Ser220Glu + Thr224Gln
Gly206Asn + Trp208Ile + Ile209Ser + Tyr218Gln +
Gly223Glu + Thr224Gly
Gly206Asn + Ser207Glu + Ile209Cys + Thr212Ser +
Thr217Pro + Ala219His
Ala204Asn + Tyr210Cys + Tyr213Asn + Tyr218Leu +
Leu221His + Ser222Glu
Gly206Pro + Tyr213Asn + Pro214Asn + Thr215Gln +
Tyr218Ser + Leu221Thr
Ala204Pro + Pro205Asn + Gly206Gln + Ile209His +
Thr212Gly + Gly223Glu
Pro205Gln + Tyr213Gly + Thr215Gly + Tyr218Ala +
Gly223Glu + Thr224Pro
Ala204His + Ser207Glu + Trp208Gly + Ile209His +
Tyr213Cys + Thr215Ser
Gly206Ser + Trp208His + Tyr213Thr + Ala219Gln +
Ser220Glu + Gly223Ser
Tyr213His + Thr215Gln + Thr217Asn + Tyr218Ala +
Ala219Glu + Leu221Ser
Ala204Asn + Pro205Ser + Gly206Asn + Ile209Leu +
Thr215Asp + Thr224Pro
Pro205Ser + Ile209Gly + Tyr213Leu + Thr217Asp +
Tyr218Asn + Ala219His
Ala204Asn + Pro205Gln + Ser207Asp + Tyr210Val +
Thr212Gly + Leu221Thr
Ala204Asn + Trp208Thr + Ile209Gln + Tyr213Pro +
Leu221Pro + Ser222Asp
Ala204Ser + Gly206Ser + Tyr213Gly + Pro214Gln +
Tyr218Val + Ser222Asp
Ala204Pro + Tyr210Cys + Tyr213Ser + Pro214Gln +
Thr215Pro + Thr217Gly
Thr212Ser + Pro214Asp + Thr217Gly + Ala219Thr +
Leu221Pro + Thr224Gln
Pro205Gln + Gly206Gln + Ser207Glu + Tyr210Gly +
Thr212Pro + Tyr218Gly
Pro205Gln + Gly206Pro + Trp208Asn + Ile209Met +
Tyr213Ser + Ala219Asp
Ala204Asn + Ser207Glu + Trp208Ala + Tyr213Asn +
Leu221Thr + Thr224Gly
Ala204Pro + Trp208His + Ile209Asn + Tyr213Leu +
Thr217Ser + Ser222Glu
Gly206Pro + Trp208Ser + Tyr210Val + Thr212Gly +
Tyr213Cys + Ala219Asp
Pro205Gly + Gly206Gln + Ile209Cys + Tyr210His +
Thr215Gln + Ala219Thr
Trp208Gly + Ile209Ser + Thr212Gln + Tyr218Met +
Leu221Ser + Gly223Ser
Pro205Asn + Ile209Asn + Thr212Asn + Thr217Glu +
Gly223Pro + Thr224Ser
Pro205Gly + Trp208Thr + Thr212Ser + Ser216Glu +
Thr217Gly + Gly223Ser
Gly206Ser + Trp208Glu + Tyr210Gln + Thr215Gly +
Thr217Gln + Leu221Pro
Gly206Ser + Ser207Glu + Trp208Leu + Thr212Asn +
Leu221Ala + Thr224Asn
Ala204Asn + Pro205Gln + Gly206Gln + Trp208Ile +
Ser216Asp + Tyr218Cys
Ala204Thr + Tyr210Cys + Tyr213Ser + Thr215Ser +
Ser216Asp + Ala219His
Trp208Leu + Ile209Asn + Thr212Gly + Thr215Ser +
Tyr218Pro + Leu221Gly
Pro205Gly + Gly206Gln + Tyr218Gly + Ala219Asn +
Leu221Gln + Thr224Ser
Pro205Gln + Trp208Val + Tyr210Pro + Thr215Gly +
Ala219Ser + Thr224Glu
Pro205Gly + Trp208Met + Ile209Ser + Thr212Asn +
Tyr218Ala + Ala219Thr
Thr212Gly + Tyr213Asn + Pro214Ser + Ser216Glu +
Thr217Pro + Leu221Thr
Ala204Gly + Trp208Pro + Ile209Pro + Tyr213Gln +
Tyr218Ser + Ser220Glu
Ala204Gly + Gly206Asn + Ile209Met + Thr212Pro +
Ala219Glu + Leu221Met
Pro205Asn + Gly206Pro + Trp208Leu + Tyr210Pro +
Thr217Gln + Tyr218Glu
Pro205Asn + Gly206Gln + Tyr213Val + Ser220Asp +
Gly223Ser + Thr224Asn
Ala204Thr + Pro205Gly + Gly206Gln + Pro214Gln +
Leu221Val + Gly223Gln
Pro205Ser + Ile209Gln + Thr212Pro + Ala219Gly +
Ser220Glu + Gly223Gln
Ala204Gly + Gly206Gln + Ile209Leu + Thr212Asn +
Pro214Gln + Thr215Ser
Gly206Asn + Trp208Ser + Thr212Ser + Pro214Asn +
Ser220Glu + Gly223Ser
Ala204His + Tyr213Leu + Pro214Asn + Thr217Pro +
Ser220Glu + Gly223Gln
Gly206Pro + Ile209Cys + Pro214Gln + Thr217Ser +
Tyr218Cys + Ala219Gln
Ala204Thr + Tyr210Ala + Thr215Gly + Thr217Gln +
Ala219Pro + Ser220Asp
Ser207Asp + Ile209Thr + Thr212Gly + Thr217Pro +
Ala219Gly + Thr224Pro
Ala204Gly + Ser207Glu + Thr212Asn + Pro214Ser +
Tyr218Ser + Ala219Ser
Pro205Gln + Gly206Gln + Thr212Ser + Tyr213Ala +
Thr215Ser + Gly223Glu
Pro205Ser + Tyr210Ala + Pro214Ser + Thr215Asn +
Ser222Asp + Gly223Glu
Ile209Pro + Tyr210Pro + Thr212Pro + Leu221Asn +
Ser222Asp + Gly223Asp
Pro205Ser + Thr212Ser + Tyr213Ile + Ala219Pro +
Ser222Glu + Gly223Asp
Ala204Asn + Ile209Cys + Tyr213Cys + Tyr218Ala +
Leu221Asp + Ser222Glu
Ile209Val + Thr212Asn + Tyr213Met + Thr217Asn +
Gly223Asp + Thr224Asp
Pro205Gly + Ile209Asn + Thr212Asn + Ser216Glu +
Thr217Glu + Tyr218Gln
Ala204His + Trp208Ser + Thr212Pro + Tyr213Pro +
Ser216Glu + Thr217Asp
Pro205Ser + Ile209Ala + Thr212Gly + Ser216Asp +
Thr217Glu + Ala219Thr
Pro205Ser + Trp208Met + Pro214Asn + Ala219Gln +
Ser220Glu + Leu221Asp
Ala204Pro + Gly206Ser + Tyr213Ile + Ser220Glu +
Leu221Asp + Gly223Ser
Gly206Pro + Tyr210Gly + Tyr213His + Thr217Glu +
Tyr218Asp + Leu221Asn
Thr212Pro + Tyr213Ser + Thr215Asp + Ser216Asp +
Tyr218Pro + Gly223Gln
Ser207Glu + Ile209Asn + Thr212Ser + Thr217Gly +
Ser222Glu + Thr224Gln
Pro205Gly + Ser207Glu + Tyr210Ser + Pro214Gln +
Ser222Asp + Gly223Asn
Gly206Pro + Ser207Asp + Trp208Ser + Pro214Ser +
Leu221Asn + Ser222Asp
Gly206Gln + Ser207Asp + Ile209Cys + Tyr210Met +
Thr217Asn + Ser222Glu
Gly206Pro + Ser207Glu + Ile209Pro + Tyr210Ile +
Leu221Asn + Ser222Glu
Pro205Ser + Ser207Glu + Trp208His + Thr215Pro +
Leu221Asn + Ser222Glu
Pro205Asn + Ser207Asp + Thr215Gln + Tyr218Ile +
Leu221Gly + Ser222Glu
Ala204Pro + Ser207Asp + Tyr210Cys + Thr212Pro +
Thr215Pro + Ser222Glu
Pro205Gly + Pro214Asp + Thr215Glu + Ser216Asp +
Thr217Pro + Gly223Gln
Ile209Thr + Thr217Gly + Ala219Glu + Ser220Asp +
Leu221Glu + Gly223Ser
Ala204Gln + Ser207Asp + Ile209Thr + Tyr218Asn +
Ser222Glu + Gly223Asp
Pro205Ser + Ser207Glu + Pro214Gly + Thr215Asn +
Ser222Asp + Gly223Glu
Pro205Asn + Gly206Pro + Trp208Asp + Thr212Gln +
Ser222Asp + Gly223Ser
Gly206Gln + Pro214Asp + Thr215Asp + Thr217Asp +
Gly223Ser + Thr224Gly
Ala204His + Ile209Thr + Ser216Asp + Thr217Asp +
Tyr218Asp + Leu221Ser
Thr212Asn + Pro214Gln + Tyr218Met + Ser222Glu +
Gly223Asp + Thr224Glu
Ala204Gln + Gly206Pro + Tyr210Glu + Pro214Gly +
Ala219Asp + Leu221Gln
Ala204Gly + Pro205Gln + Trp208Asp + Ile209Gln +
Pro214Gly + Leu221Glu
Ala204Asn + Gly206Gln + Ser207Glu + Trp208His +
Leu221Asp + Ser222Asp
Trp208Gly + Tyr213Ser + Pro214Ser + Thr215Glu +
Thr217Asp + Tyr218Ala
Ala204Asn + Pro205Ser + Tyr210Pro + Pro214Asp +
Ser216Glu + Tyr218Ile
Gly206Gln + Ile209Leu + Thr212Gly + Pro214Asp +
Ser216Glu + Leu221His
Pro205Gln + Trp208Glu + Tyr210Asp + Thr212Gln +
Tyr213Asn + Thr215Ser
Ser207Asp + Thr212Pro + Thr215Gly + Thr217Gln +
Leu221Met + Gly223Asp
Ala204Asn + Pro205Gln + Ser207Glu + Trp208Met +
Ala219Pro + Gly223Asp
Ala204Thr + Ser207Asp + Thr212Gly + Ala219Asn +
Gly223Asp + Thr224Asn
Ser207Asp + Pro214Asn + Thr215Gly + Tyr218Ala +
Leu221Ser + Gly223Asp
Ser207Glu + Thr212Asn + Tyr213Gln + Tyr218Pro +
Ser220Glu + Leu221Asp
Ala204Asn + Gly206Ser + Ser207Asp + Tyr210Thr +
Ser220Asp + Leu221Asp
Gly206Ser + Thr212Asn + Thr215Pro + Tyr218Val +
Leu221Asp + Gly223Asp
Trp208Met + Tyr210Thr + Thr212Asn + Ala219Gln +
Leu221Asp + Gly223Asp
Gly206Ser + Ser207Glu + Pro214Ser + Ala219Asn +
Ser220Glu + Ser222Glu
Ala204His + Ser207Glu + Ala219Ser + Ser220Glu +
Leu221His + Ser222Asp
Pro205Ser + Ser207Glu + Tyr213His + Thr217Pro +
Ser220Glu + Ser222Glu
Ser207Glu + Ile209Met + Tyr210Gly + Tyr213Leu +
Ser220Glu + Ser222Asp
Ser207Asp + Tyr213Pro + Pro214Gln + Ser220Glu +
Ser222Glu + Gly223Pro
Gly206Ser + Trp208Gln + Tyr210Glu + Thr212Asn +
Thr215Gly + Leu221Glu
Pro205Gly + Thr212Ser + Tyr218Leu + Ala219Gln +
Ser220Glu + Ser222Glu
Trp208Phe + Thr212Asn + Pro214Ser + Ser220Glu +
Ser222Asp + Gly223Gln
Ala204Gly + Gly206Pro + Tyr210Ser + Tyr218Cys +
Ser220Glu + Ser222Asp
Pro205Ser + Trp208Leu + Tyr213Ala + Thr217Ser +
Ser220Asp + Ser222Asp
Pro205Gly + Trp208His + Tyr210His + Ser220Glu +
Leu221Gln + Ser222Asp
Pro205Gly + Thr212Gln + Ala219Thr + Ser220Glu +
Ser222Asp + Gly223Pro
Ala204Ser + Gly206Pro + Tyr210Gly + Ser220Glu +
Leu221Ser + Ser222Asp
Ile209Ser + Tyr210Ser + Thr212Asn + Tyr213Cys +
Ser220Asp + Ser222Glu
Ala204Asn + Pro205Gly + Ser207Asp + Ile209Ser +
Tyr213Val + Leu221Glu
Ala204Asn + Gly206Pro + Thr215Glu + Ser216Glu +
Thr217Asn + Tyr218Glu
Gly206Pro + Ile209Ser + Tyr210His + Thr217Gly +
Ser222Glu + Thr224Asp
Gly206Gln + Thr217Gly + Ser220Asp + Ser222Glu +
Gly223Glu + Thr224Ser
Gly206Gln + Trp208Gin + Ile209Gln + Ser216Asp +
Tyr218Asp + Ala219Glu
Gly206Asn + Thr212Pro + Pro214Ser + Thr217Glu +
Tyr218Glu + Ser220Glu
Gly206Gln + Trp208Ser + Tyr210Asp + Pro214Gln +
Thr217Glu + Ala219Asp
Gly206Ser + Ser207Glu + Trp208Pro + Tyr210Asp +
Ala219Thr + Ser222Asp
Trp208Gly + Tyr210His + Thr212Ser + Pro214Glu +
Tyr218Asp + Leu221Ile
Ala204Gln + Gly206Gln + Tyr210Gly + Pro214Glu +
Thr217Pro + Tyr218Glu
Ala204His + Pro214Glu + Thr215Gln + Thr217Gln +
Tyr218Glu + Leu221Pro
Ser207Asp + Ile209Cys + Thr215Pro + Tyr218His +
Ala219Thr + Ser220Glu
Pro205Asn + Ser207Glu + Trp208Tyr + Ile209Asn +
Thr217Gln + Ser220Glu
Ser207Asp + Pro214Ser + Thr215Asn + Thr217Asn +
Ser220Glu + Leu221Ser
Pro205Gly + Ser207Asp + Tyr210Ser + Ser220Asp +
Gly223Pro + Thr224Ser
Gly206Gln + Ser207Glu + Ile209Gln + Ser220Asp +
Leu221Ala + Thr224Ser
Ala204Ser + Pro205Gly + Ser207Asp + Thr212Ser +
Thr215Gln + Ser220Glu
Pro205Ser + Ser207Asp + Thr217Gln + Ala219His +
Ser220Glu + Gly223Glu
Ser207Glu + Thr215Gln + Tyr218Val + Ser220Asp +
Gly223Glu + Thr224Asn
Pro205Gly + Ile209Pro + Tyr210Asp + Ala219Asp +
Ser222Asp + Gly223Ser
Gly206Asn + Tyr210Gln + Pro214Asn + Thr215Glu +
Tyr218Glu + Leu221Ala
Ile209Asn + Tyr210Asp + Thr212Gln + Ser222Glu +
Gly223Pro + Thr224Asn
Ala204Gly + Gly206Gln + Ser220Asp + Leu221Asp +
Gly223Asn + Thr224Glu
Gly206Pro + Thr212Pro + Thr217Pro + Tyr218Asn +
Leu221Glu + Thr224Glu
Ile209His + Tyr210Leu + Tyr213Leu + Pro214Asp +
Thr217Asp + Ser220Glu
Ile209Asn + Tyr210Ile + Thr212Asn + Thr215Gly +
Ser220Asp + Gly223Glu
Gly206Gln + Tyr210Ala + Thr215Asn + Ser216Glu +
Thr217Asp + Ser220Asp
Trp208Thr + Tyr213Pro + Tyr218His + Ala219Glu +
Leu221Cys + Ser222Asp
Ala204Gly + Trp208Gln + Thr212Gln + Ser216Asp +
Ala219Glu + Gly223Ser
Gly206Ser + Pro214Gly + Ser216Asp + Tyr218Pro +
Ala219Glu + Leu221Pro
Pro205Asn + Tyr210Asn + Thr217Glu + Ala219Gln +
Ser220Glu + Gly223Gln
Ala204Thr + Tyr213Ala + Pro214Gln + Thr215Gln +
Thr217Asp + Ser220Glu
Trp208Gln + Tyr210His + Thr217Asp + Tyr218Met +
Ser220Asp + Thr224Ser
Ala204Asn + Gly206Pro + Tyr210Asp + Pro214Glu +
Ser220Glu + Thr224Asn
Tyr213Ile + Ser216Glu + Tyr218His + Ala219Glu +
Leu221Asp + Thr224Ser
Pro205Ser + Trp208Glu + Tyr218Glu + Leu221Gly +
Ser222Glu + Thr224Gly
Ser207Asp + Tyr213Met + Pro214Gly + Thr217Gln +
Tyr218Asp + Ala219Glu
Trp208Phe + Ala219Asp + Leu221Ala + Ser222Asp +
Gly223Asn + Thr224Glu
Gly206Pro + Ile209His + Pro214Glu + Ser220Asp +
Leu221Glu + Thr224Pro
Trp208Tyr + Ile209Asn + Thr212Asn + Thr217Glu +
Leu221Glu + Ser222Asp
Pro205Gly + Ser216Glu + Thr217Glu + Ala219Gln +
Leu221Glu + Gly223Gln
Pro214Asn + Thr217Pro + Ala219Asp + Ser220Asp +
Leu221Gln + Thr224Asp
Ala204His + Gly206Asn + Ile209His + Pro214Glu +
Ser216Asp + Ser220Glu
Ser207Asp + Tyr210Glu + Thr217Asp + Tyr218Ala +
Leu221Ile + Thr224Pro
Thr212Gly + Tyr213Ala + Pro214Glu + Leu221Glu +
Ser222Asp + Thr224Ser
Pro205Gln + Gly206Asn + Thr212Gln + Tyr218Glu +
Ser222Asp + Gly223Asp
Pro205Gln + Thr212Gly + Tyr213Ala + Thr217Glu +
Tyr218Glu + Ser222Glu
Ile209Gln + Tyr213Ala + Pro214Glu + Ala219Asp +
Ser222Asp + Thr224Pro
Ala204Gly + Tyr210Pro + Pro214Glu + Ala219Glu +
Leu221Asn + Ser222Asp
Gly206Pro + Thr212Asn + Tyr213Thr + Pro214Asp +
Ser220Asp + Ser222Glu
Ala204Thr + Tyr213Ser + Pro214Asp + Ala219Asn +
Ser220Asp + Ser222Glu
Ala204His + Gly206Asn + Tyr210Pro + Pro214Glu +
Ser220Glu + Ser222Glu
Ser207Asp + Trp208Met + Pro214Glu + Thr215Asp +
Thr217Ser + Gly223Pro
Trp208Cys + Ile209Ser + Pro214Glu + Ser222Asp +
Gly223Asp + Thr224Gly
Pro205Asn + Thr212Asn + Tyr213Leu + Thr215Asp +
Ser222Asp + Gly223Glu
...
Table 28
Ring 6 - seven substituted mutant
Gly206Asn + Tyr210Gly + Thr212Gln + Thr215Gln +
Tyr218Ile + Leu221Ile + Thr224Gly
Ala204Ser + Pro205Ser + Ile209Met + Tyr213Ser +
Tyr218His + Ala219Gln + Leu221Asn
Ala204Gly + Trp208Gln + Thr212Gln + Ser216Asp +
Tyr218Gln + Leu221Met + Gly223Ser
Gly206Gln + Ile209Leu + Tyr210Ala + Thr212Gly +
Tyr213Gly + Ser216Asp + Gly223Gln
Ala204Gln + Pro205Asn + Gly206Asn + Trp208Ile +
Tyr210Gln + Thr215Gln + Ala219Asp
Ala204Asn + Pro205Gln + Ile209Ala + Tyr213Leu +
Thr217Glu + Tyr218Met + Leu221Gln
Pro205Gly + Ile209Gln + Thr212Ser + Ala219Gln +
Ser220Glu + Leu221Cys + Thr224Ser
Gly206Asn + Trp208Cys + Thr212Gly + Tyr213Gly +
Ser216Asp + Thr217Gly + Leu221His
Ala204Gln + Pro205Ser + Tyr210His + Thr212Pro +
Tyr218Pro + Ala219Ser + Thr224Glu
Ala204Gly + Gly206Asn + Tyr210Cys + Tyr213Thr +
Thr215Gly + Gly223Asp + Thr224Asn
Ala204Gln + Pro205Ser + Gly206Gln + Thr212Asn +
Tyr218Cys + Ala219His + Gly223Glu
Ala204Ser + Gly206Asn + Ile209Gly + Pro214Gly +
Thr217Gly + Leu221Val + Thr224Pro
Pro205Gly + Ile209Gln + Pro214Asn + Tyr218Ile +
Ala219Gly + Leu221Met + Ser222Asp
Ala204Asn + Trp208Ala + Ile209Gln + Pro214Gly +
Thr217Glu + Tyr218Leu + Gly223Asn
Gly206Asn + Tyr210Glu + Tyr213Gly + Thr217Gln +
Tyr218Leu + Ala219Thr + Thr224Ser
Gly206Pro + Ile209His + Tyr213Asn + Pro214Asn +
Thr215Gln + Tyr218Ser + Leu221Thr
Pro205Gly + Gly206Ser + Trp208His + Tyr213Thr +
Ala219Gln + Ser220Glu + Gly223Ser
Pro205Gln + Gly206Ser + Trp208Val + Tyr210Leu +
Thr212Asn + Tyr218Met + Ser220Glu
Ala204His + Gly206Asn + Tyr210Ser + Pro214Ser +
Thr217Gln + Tyr218His + Ser222Asp
Gly206Gln + Tyr213Asn + Thr215Gly + Ser216Glu +
Thr217Gly + Tyr218His + Gly223Asn
Gly206Gln + Ser207Glu + Tyr210Gly + Thr212Pro +
Tyr213Met + Gly223Pro + Thr224Pro
Ala204Asn + Trp208Thr + Ile209Gln + Tyr213Pro +
Thr217Ser + Leu221Pro + Ser222Asp
Ala204Ser + Gly206Gln + Trp208Asn + Thr212Ser +
Ala219Gln + Ser220Glu + Leu221Asn
Pro205Gly + Gly206Gln + Ile209Asn + Tyr213Val +
Thr215Gln + Thr217Ser + Ala219Thr
Ala204Ser + Pro205Gln + Ile209Asn + Thr212Asn +
Thr217Glu + Gly223Pro + Thr224Ser
Thr212Gly + Tyr213Ile + Pro214Gly + Tyr218Gly +
Ala219Pro + Leu221Asn + Thr224Glu
Ala204Asn + Tyr210Asp + Thr212Pro + Tyr213Asn +
Thr217Asn + Tyr218Cys + Leu221His
Ala204Gln + Ile209Cys + Tyr210Gln + Thr212Gly +
Tyr213Gln + Gly223Pro + Thr224Asp
Pro205Gln + Gly206Gln + Trp208Thr + Tyr210Leu +
Thr215Gly + Thr217Gly + Tyr218Leu
Tyr210Ala + Tyr213Val + Pro214Gln + Ala219Ser +
Leu221Cys + Ser222Glu + Thr224Asn
Ala204Asn + Gly206Pro + Ser207Asp + Trp208His +
Ile209His + Pro214Gln + Leu221Gln
Ala204Asn + Gly206Asn + Trp208Ile + Ile209Asn +
Ser216Glu + Ala219Pro + Gly223Asn
Ala204Ser + Gly206Ser + Ile209Ala + Thr212Ser +
Pro214Gln + Tyr218Asp + Leu221His
Gly206Asn + Ile209Pro + Tyr213Cys + Thr215Gln +
Ser216Glu + Thr217Pro + Ala219His
Ala204Gln + Trp208His + Tyr210Gly + Thr212Gln +
Tyr218Met + Ala219Asn + Ser220Glu
Ala204Pro + Ser207Asp + Tyr213Val + Pro214Gly +
Thr215Gly + Tyr218Ala + Leu221Gln
Pro205Asn + Gly206Pro + Trp208Leu + Tyr210Pro +
Pro214Asn + Thr217Gln + Tyr218Glu
Pro205Asn + Gly206Gln + Tyr213Val + Ala219Gln +
Ser220Asp + Gly223Ser + Thr224Asn
Gly206Pro + Ile209Cys + Tyr210Ser + Thr212Asn +
Tyr213Cys + Pro214Gln + Tyr218Cys
Ala204His + Trp208Asn + Thr212Pro + Pro214Gln +
Thr215Asn + Thr217Gly + Thr224Asp
Pro205Ser + Gly206Ser + Tyr210Ser + Thr215Pro +
Ala219Asn + Leu221Met + Ser222Asp
Ala204Ser + Gly206Gln + Trp208Pro + Thr212Asn +
Thr215Glu + Tyr218Ile + Gly223Asn
Ala204Ser + Pro205Asn + Trp208Tyr + Thr215Gly +
Tyr218Pro + Ser220Glu + Thr224Gly
Ala204Asn + Tyr210His + Pro214Asn + Tyr218Pro +
Ala219Gln + Ser220Glu + Leu221Ile
Ala204Gly + Gly206Asn + Ser207Asp + Thr212Asn +
Tyr213Leu + Thr215Pro + Gly223Pro
Ala204Asn + Tyr210Met + Thr212Gln + Pro214Gly +
Ala219Gly + Ser222Asp + Gly223Gln
Tyr210Pro + Thr212Gly + Tyr213Leu + Thr215Gly +
Thr217Gly + Ala219Glu + Ser220Asp
Gly206Ser + Trp208Asn + Ile209Pro + Ala219Asp +
Ser220Asp + Gly223Ser + Thr224Gly
Pro205Ser + Tyr210Cys + Tyr213Thr + Pro214Asp +
Thr215Asp + Tyr218Val + Leu221Ser
Trp208His + Ile209Val + Thr212Pro + Tyr213Leu +
Thr217Ser + Ser222Glu + Gly223Glu
Pro205Gly + Gly206Gln + Tyr210Asn + Tyr213Gly +
Thr217Gly + Ser222Glu + Gly223Glu
Ala204Thr + Thr212Gln + Tyr213Gln + Thr217Ser +
Ser222Asp + Gly223Asp + Thr224Pro
Pro205Gly + Ile209Cys + Tyr213Val + Pro214Gln +
Thr215Pro + Ser222Glu + Gly223Asp
Trp208Ser + Ile209Ser + Ser216Glu + Thr217Glu +
Tyr218Gly + Ala219His + Gly223Pro
Gly206Pro + Tyr210Gln + Thr212Pro + Tyr213Leu +
Ser216Glu + Thr217Asp + Leu221Pro
Trp208Met + Ile209Gln + Tyr210Met + Tyr218Gln +
Ser220Glu + Leu221Glu + Thr224Ser
Ile209Gln + Thr212Ser + Tyr213Val + Thr215Asp +
Ser216Glu + Tyr218Met + Ala219Pro
Tyr213Pro + Pro214Gln + Thr215Asp + Ser216Glu +
Thr217Asp + Tyr218Met + Leu221Ala
Ala204His + Pro205Gly + Ser207Glu + Trp208His +
Tyr210His + Tyr213Cys + Ser222Asp
Gly206Pro + Ser207Asp + Trp208Ser + Pro214Ser +
Leu221Asn + Ser222Asp + Gly223Pro
Ser207Glu + Trp208Tyr + Ile209Gly + Tyr213Thr +
Pro214Ser + Tyr218Met + Ser222Glu
Pro205Ser + Ser207Asp + Trp208Ser + Thr212Gly +
Tyr213Asn + Tyr218Gln + Ser222Asp
Ala204Thr + Gly206Asn + Trp208Thr + Thr212Gln +
Pro214Glu + Thr215Asp + Ser216Asp
Ala204Thr + Gly206Asn + Ser207Glu + Tyr210Ile +
Leu221Thr + Ser222Glu + Gly223Glu
Ala204His + Ser207Glu + Thr215Gln + Thr217Gln +
Tyr218Asn + Ser222Glu + Gly223Glu
Ala204Gln + Trp208Asp + Tyr210Thr + Thr212Ser +
Thr217Asn + Ser222Asp + Gly223Asn
Ile209Thr + Ser216Asp + Thr217Asp + Tyr218Asp +
Leu221Ser + Gly223Ser + Thr224Gly
Ala204Asn + Gly206Gln + Ser207Glu + Trp208His +
Thr212Ser + Leu221Asp + Ser222Asp
Gly206Ser + Ser207Asp + Tyr210Val + Thr212Gln +
Tyr218Ile + Leu221Asp + Ser222Asp
Ala204Ser + Gly206Pro + Pro214Gly + Thr215Asp +
Thr217Asp + Tyr218Pro + Gly223Pro
Gly206Gln + Ile209His + Pro214Asp + Thr215Pro +
Ser216Asp + Leu221Gly + Thr224Ser
Gly206Asn + Ser207Glu + Trp208Asp + Ile209Gly +
Tyr213Gly + Ser220Glu + Ser222Glu
Pro205Ser + Ser207Asp + Ile209Asn + Tyr213Met +
Thr217Gln + Ala219His + Gly223Glu
Pro205Gly + Gly206Gln + Ser207Glu + Ala219Pro +
Ser220Asp + Leu221Glu + Thr224Ser
Trp208Met + Tyr210Thr + Thr212Asn + Ala219Gln +
Leu221Asp + Gly223Asp + Thr224Gln
Pro205Ser + Ser207Glu + Tyr213His + Thr217Pro +
Ala219Ser + Ser220Glu + Ser222Glu
Ser207Asp + Tyr210Met + Pro214Ser + Tyr218Asn +
Ser220Glu + Leu221Cys + Ser222Glu
Ala204Pro + Ser207Glu + Pro214Gln + Ser220Asp +
Leu221His + Ser222Asp + Thr224Ser
Ser207Glu + Ile209Met + Tyr210Gly + Tyr213Leu +
Thr215Gln + Ser220Glu + Ser222Asp
Gly206Pro + Ser207Asp + Ile209Ser + Tyr210His +
Thr217Gly + Ser222Glu + Thr224Asp
Pro205Asn + Tyr210Cys + Tyr213Gly + Thr217Asn +
Tyr218Met + Ser220Glu + Ser222Asp
Ile209Gly + Thr212Pro + Thr215Asn + Thr217Gly +
Ala219His + Ser220Glu + Ser222Glu
Ala204Gln + Gly206Gln + Thr212Pro + Ser220Glu +
Leu221Val + Ser222Asp + Thr224Gln
Ala204Gln + Pro205Ser + Gly206Ser + Trp208Gln +
Thr215Pro + Ser220Glu + Ser222Glu
Ser207Glu + Trp208Leu + Tyr210Ile + Thr212Gly +
Tyr218Cys + Leu221Asp + Gly223Asn
Pro205Gly + Gly206Pro + Ser207Asp + Ile209Met +
Leu221Asp + Ser222Glu + Thr224Asp
Pro205Gly + Thr215Asn + Thr217Pro + Tyr218Val +
Leu221Thr + Ser222Glu + Thr224Asp
Trp208Phe + Tyr213Met + Thr215Asn + Tyr218Asp +
Ala219Pro + Ser220Glu + Thr224Gly
Ala204Pro + Pro205Gly + Trp208Leu + Thr217Gln +
Leu221Asp + Ser222Glu + Thr224Asp
Ile209Ala + Thr212Gln + Thr217Gln + Tyr218Thr +
Ser220Glu + Leu221Asp + Gly223Glu
Ala204Asn + Ile209Cys + Tyr213Cys + Tyr218Ala +
Ala219Glu + Leu221Asp + Ser222Glu
Gly206Ser + Ser207Glu + Trp208His + Tyr210Asp +
Tyr218Val + Ala219Thr + Ser222Asp
Pro205Gly + Ser207Asp + Trp208Thr + Thr212Ser +
Thr217Gly + Ser220Glu + Gly223Ser
Ser207Glu + Trp208Asn + Tyr210Pro + Pro214Asn +
Tyr218Ser + Ser220Asp + Gly223Ser
Ala204Gln + Ser207Asp + Trp208Gly + Ile209Ala +
Thr212Asn + Ser220Glu + Gly223Pro
Pro205Gln + Ser207Asp + Ile209Gln + Pro214Asn +
Thr215Gln + Ser220Asp + Thr224Gly
Pro205Asn + Ser207Glu + Ile209Val + Thr212Gly +
Tyr213Pro + Ala219Asn + Thr224Glu
Ala204Gly + Ser207Glu + Ile209Ala + Thr212Pro +
Tyr213Cys + Ala219Glu + Ser220Asp
Pro205Ser + Trp208Glu + Thr212Asn + Tyr218Glu +
Ala219His + Leu221Glu + Ser222Glu
Pro205Ser + Ile209Pro + Tyr210Asp + Thr212Ser +
Tyr213Ile + Ala219Pro + Ser222Glu
Gly206Ser + Trp208Thr + Tyr210Ala + Pro214Asp +
Tyr218Met + Ala219Glu + Ser220Asp
Ile209Leu + Pro214Glu + Thr215Pro + Ala219Glu +
Ser220Glu + Gly223Pro + Thr224Gly
Trp208Tyr + Thr212Asn + Thr217Glu + Ala219Gly +
Ser220Asp + Leu221Glu + Ser222Asp
Ala204Thr + Tyr210Pro + Tyr213Asn + Pro214Glu +
Tyr218Asp + Ser220Asp + Thr224Gly
Gly206Pro + Thr212Pro + Pro214Gly + Thr215Pro +
Ser220Asp + Leu221Asp + Thr224Glu
Thr212Asn + Pro214Gln + Tyr218Met + Ala219Asp +
Ser222Glu + Gly223Asp + Thr224Glu
Trp208Gly + Tyr210Pro + Thr212Gly + Ser220Glu +
Leu221Met + Gly223Asp + Thr224Glu
Gly206Gln + Tyr213Asn + Pro214Asn + Thr217Asp +
Ala219His + Ser220Glu + Leu221Asp
Pro205Gln + Ile209Pro + Tyr210Asn + Tyr218Thr +
Ala219Glu + Ser220Asp + Gly223Asp
Ala204Thr + Ser207Asp + Tyr210Asp + Tyr213Met +
Ala219Asn + Ser220Glu + Thr224Asp
Pro205Ser + Trp208Pro + Ile209Pro + Tyr213Ile +
Ala219Asp + Ser222Asp + Gly223Asp
Ala204Asn + Thr212Pro + Thr217Glu + Tyr218Asp +
Ser220Glu + Ser222Asp + Thr224Gln
Gly206Pro + Ser207Asp + Trp208Val + Tyr210Thr +
Tyr213Ala + Ser220Asp + Thr224Asp
Pro205Gly + Ser207Glu + Tyr210Ile + Pro214Ser +
Thr217Gly + Ser220Asp + Thr224Glu
Ala204Thr + Tyr210Cys + Thr212Pro + Tyr218Ile +
Ser220Glu + Leu221Ser + Gly223Glu
Ala204Gln + Trp208Pro + Pro214Asn + Ala219Thr +
Ser220Glu + Gly223Asp + Thr224Gln
Pro205Gln + Tyr213Gly + Thr215Gly + Tyr218Ala +
Ser220Asp + Gly223Glu + Thr224Pro
Pro205Gly + Gly206Ser + Thr217Pro + Ala219His +
Ser220Asp + Leu221Cys + Gly223Asp
Pro205Ser + Tyr210Thr + Thr212Asn + Tyr213Cys +
Pro214Ser + Ala219Asp + Ser222Asp
Trp208Asn + Thr217Glu + Tyr218Cys + Ala219Glu +
Ser220Asp + Gly223Glu + Thr224Ser
Pro205Ser + Gly206Pro + Trp208Pro + Ile209Ala +
Thr215Asp + Tyr218Asp + Ser220Asp
Trp208Thr + Thr212Gly + Tyr213Ile + Thr215Asp +
Leu221Asp + Ser222Glu + Gly223Glu
Ala204Gly + Pro205Gly + Tyr210Glu + Thr217Glu +
Tyr218Cys + Ala219Gly + Leu221Val
Ser207Asp + Thr215Pro + Thr217Asp + Tyr218Ile +
Leu221Ala + Ser222Glu + Gly223Asp
Gly206Pro + Trp208Glu + Tyr210Cys + Pro214Gln +
Thr217Asp + Ser220Asp + Gly223Gln
Trp208Thr + Tyr213Pro + Pro214Ser + Ser216Asp +
Tyr218Met + Ala219Asp + Thr224Pro
Ala204Asn + Trp208Ala + Tyr213Asn + Ser216Asp +
Ala219Glu + Leu221Cys + Thr224Gly
Gly206Ser + Tyr210Ser + Pro214Gly + Ser216Asp +
Tyr218Cys + Ala219Glu + Leu221Pro
Ala204Thr + Tyr210Gln + Thr212Gln + Tyr213Ala +
Pro214Gln + Thr217Asp + Ser220Glu
Pro205Gln + Gly206Ser + Ser207Glu + Tyr210Ser +
Ser216Asp + Thr217Glu + Tyr218Glu
Tyr210Met + Tyr213Met + Ser216Asp + Ala219Glu +
Ser220Glu + Leu221Cys + Ser222Glu
Ala204Gln + Ile209His + Ser216Glu + Thr217Ser +
Ala219Glu + Ser220Asp + Ser222Glu
Ile209Ser + Tyr210Leu + Tyr213Leu + Pro214Asp +
Thr217Asp + Ser220Glu + Leu221Glu
Ala204His + Pro205Gln + Pro214Asn + Tyr218Gln +
Ala219Asp + Leu221Glu + Thr224Asp
Ala204Gly + Ser207Glu + Pro214Glu + Tyr218Pro +
Ser220Glu + Ser222Asp + Thr224Asn
Ala204Pro + Pro205Gly + Trp208Glu + Ile209Ser +
Tyr210Asp + Ala219Thr + Thr224Glu
Ala204Gly + Ser207Glu + Trp208Glu + Tyr210Asp +
Ser216Glu + Thr217Gln + Thr224Gly
Trp208Ala + Tyr210Cys + Thr212Ser + Thr217Glu +
Ala219Gln + Ser220Asp + Ser222Glu
Gly206Asn + Ser207Glu + Trp208Glu + Thr212Ser +
Ser216Glu + Leu221Met + Gly223Glu
Ala204Thr + Ser207Asp + Ile209Cys + Thr215Asp +
Tyr218Ile + Ser220Asp + Leu221Asp
Ser207Asp + Thr212Pro + Pro214Gln + Ser216Glu +
Tyr218Val + Ser220Asp + Ser222Asp
Ile209Pro + Thr212Gly + Tyr213Ser + Pro214Glu +
Thr215Glu + Ala219Gln + Ser220Glu
Pro205Asn + Ser207Glu + Ile209Met + Pro214Ser +
Ser216Asp + Ala219Glu + Leu221Asp
Ala204Thr + Ser207Glu + Tyr210Leu + Ser216Glu +
Ala219Asp + Leu221Asp + Gly223Asn
Gly206Asn + Ser207Glu + Pro214Gly + Thr215Glu +
Thr217Glu + Tyr218Thr + Ala219Glu
Gly206Gln + Ser207Glu + Tyr210Ala + Thr215Asn +
Thr217Asp + Ser220Asp + Leu221Ala
Ser207Glu + Trp208Leu + Tyr213Val + Pro214Asp +
Ala219Glu + Ser222Glu + Thr224Pro
Ala204Thr + Ser207Asp + Trp208Leu + Tyr210Asp +
Thr212Pro + Thr215Asp + Leu221Glu
Pro205Gln + Ser207Asp + Ile209Ala + Thr217Asn +
Tyr218Glu + Ala219Asp + Gly223Asp
Ser207Glu + Ile209Thr + Tyr213Gly + Ser216Asp +
Ala219Asp + Ser222Glu + Gly223Pro
Gly206Ser + Ser207Asp + Ile209Ala + Thr212Gln +
Thr217Glu + Ala219Glu + Leu221Asn
Pro205Asn + Tyr210Glu + Thr217Asp + Tyr218Ala +
Leu221Ile + Ser222Glu + Thr224Pro
Ser216Asp + Thr217Asp + Tyr218Cys + Ala219His +
Leu221Glu + Ser222Glu + Gly223Asn
Ala204Gln + Trp208Asp + Pro214Gln + Ser216Glu +
Thr217Gln + Ser220Asp + Gly223Asp
Pro205Gln + Tyr210Leu + Tyr213Thr + Ser216Glu +
Tyr218Glu + Ser220Glu + Gly223Glu
Pro214Gly + Thr217Asp + Tyr218Gly + Ala219Glu +
Leu221Asn + Ser222Glu + Thr224Glu
Gly206Pro + Ser207Asp + Trp208Asp + Thr212Gln +
Thr217Asp + Gly223Ser + Thr224Glu
Ala204Pro + Pro205Ser + Gly206Pro + Ile209Val +
Tyr213Pro + Thr215Asp + Ala219Glu
Ala204Pro + Gly206Pro + Tyr210Val + Pro214Glu +
Ser220Glu + Ser222Glu + Thr224Pro
Ala204Gly + Gly206Pro + Thr212Gln + Pro214Glu +
Ser220Glu + Leu221Val + Ser222Asp
Ala204Asn + Gly206Gln + Ile209Ser + Tyr210Ala +
Pro214Glu + Ser220Glu + Ser222Asp
Pro205Gln + Trp208Gln + Pro214Glu + Thr217Pro +
Leu221Met + Ser222Asp + Gly223Glu
Ala204Thr + Pro205Asn + Pro214Asp + Thr215Pro +
Leu221Cys + Ser222Asp + Gly223Asp
Ile209Pro + Tyr210Pro + Thr212Pro + Thr217Asp +
Leu221Asn + Ser222Asp + Gly223Asp
Gly206Gln + Trp208Thr + Ile209Ser + Tyr213Met +
Thr215Glu + Ser222Asp + Gly223Glu
Pro205Asn + Trp208Ser + Thr212Gly + Tyr213Asn +
Thr215Asp + Ser222Asp + Gly223Glu
Tyr210Gly + Thr212Pro + Pro214Gly + Ser216Asp +
Ala219His + Leu221Glu + Ser222Asp
Pro205Gly + Gly206Pro + Ile209His + Thr215Asp +
Ala219Gly + Leu221Glu + Ser222Glu
Pro205Gln + Tyr210Gly + Thr212Asn + Ser216Asp +
Ala219Pro + Ser220Glu + Leu221Asp
Gly206Ser + Trp208Glu + Tyr210Gln + Thr215Gly +
Ser216Glu + Thr217Glu + Leu221Pro
Pro205Gln + Gly206Gln + Ser216Glu + Thr217Asp +
Leu221Ala + Ser222Glu + Thr224Pro
Gly206Ser + Ser207Glu + Trp208Asp + Ile209Leu +
Thr215Asp + Ser216Glu + Tyr218Gln
Tyr210His + Thr212Gln + Thr215Asp + Ser216Glu +
Leu221Glu + Gly223Ser + Thr224Pro
Ala204Ser + Pro205Ser + Gly206Asn + Thr215Asp +
Ser216Glu + Tyr218Val + Gly223Asp
Ala204Gln + Gly206Asn + Ser207Glu + Trp208Pro +
Pro214Asp + Thr215Asp + Ser222Asp
Ser207Asp + Tyr210Gln + Thr212Gln + Thr215Asp +
Ser216Asp + Leu221Gly + Ser222Asp
Ile209Met + Tyr210Leu + Thr217Glu + Tyr218Thr +
Ser220Glu + Gly223Glu + Thr224Asn
Pro205Ser + Ser207Glu + Trp208His + Thr215Pro +
Thr217Asp + Leu221Asn + Ser222Glu
Ala204Thr + Ser207Glu + Thr212Gly + Tyr213Leu +
Pro214Asn + Ser216Glu + Ser222Glu
Ala204Pro + Ser207Asp + Tyr210Leu + Thr212Gln +
Tyr213Thr + Thr215Glu + Ser222Glu
...
Table 29
Polycyclic double mutant
Leu104Gly + Tyr210Pro
Asn 66Gln + Thr217Glu
Gly 67Ser + Gly 69Ser
Val103Gln + Gly223Asp
Trp112Cys + Thr217Gly
Ala164Glu + Trp208Gln
Leu134Ile + Trp208Gln
Ala219Gly + Ser220Glu
Asn 66Asp + Leu104Gly
Ala168Thr + Ser216Glu
Leul04Ala + Ser109Glu
Thr111Gln + Val115Ala
Ser109Asp + Tyr210Pro
Gly 69Ser + Serl91Asp
Val103Asp + Gly206Gln
Gly 67Glu + Pro214Asn
Trp208Ile + Thr215Asp
Ser107Glu + Thr113Gly
Gly108Ser + Leu221Glu
Ser 70Glu + Pro169Asn
Gly165Gln + Leu221Asp
Gly108Glu + Ala164Gly
Leu104His + Thr167Pro
Ala164His + Ser220Glu
Thr195Gln + Ser222Asp
Trp208His + Ala219Pro
Gly 69Glu + Asn106Gln
Trp112Cys + Thr113Pro
Gly 67Gln + Trp208Asp
Ala114Glu + Leu134Ile
Ser109Glu + Gly136Ser
Gly110Ser + Ser207Glu
Val103Ala + Thr212Ser
Ala114Glu + Thr167Pro
Thr195Glu + Ala204Thr
Gly 67Ser + Thr217Glu
Trp208Tyr + Ser220Glu
Ala168His + Thr217Asp
Ala168Glu + Tyr213Asn
Gly110Pro + Ser220Asp
Tyr171Asn + Leu221Met
Thr 73Asp + Leu134Ser
Thr137Asn + Thr217Pro
Ser 70Asp + Ala168Thr
Thr167Glu + Tyr210Pro
Thr195Glu + Tyr210Gly
Tyr210Gln + Thr217Glu
Gly 67Glu + Val115Cys
Ser 70Glu + Ala219Thr
Gly136Pro + Leu221Ala
Gly 67Ser + Thr195Ser
Phe193His + Ser222Asp
Asn 68Glu + Tyr210Ser
Gly165Asp + Pro169Ser
Trp208Pro + Thr215Gly
Thr 73Gly + Leu104Gly
Thr113Asn + Ser216Glu
Gly 72Gln + Gly139Asp
Tyr210Ile + Leu221Gly
Thr 73Pro + Tyr171Asp
Leu104Gln + Thr137Gly
Gly 69Pro + Tyr210Ala
Thr217Gly + Gly223Glu
Thr195Asp + Tyr213Ser
Gly 72Asn + Ala219Asn
Val138Pro + Tyr210Ala
Tyr218Met + Gly223Asn
Ser220Glu + Leu221Asn
Trp112Ala + Gly139Asn
Gly135Glu + Leu221Gly
Thr113Asn + Thr217Ser
Thr195Asn + Thr217Asp
Tyr210Val + Ser220Glu
Val138Gly + Ala219Asp
Asn166Glu + Leu221His
Gly165Gln + Leu221His
Thr113Gln + Ser192Asp
Asn 66Asp + Thr 73Ser
Thr167Gln + Thr217Gly
Val115Pro + Gly135Ser
Ala219Gln + Gly223Asp
Trp208His + Thr217Asn
Trp208Leu + Tyr210Val
Gly108Asn + Ser191Glu
Ser107Glu + Tyr210Ala
Asn 68Gln + Ser220Glu
Trp112Cys + Leu221Asn
Gly108Gln + Ser109Asp
Val103Met + Ala168His
Ala164Pro + Ser192Glu
Pro214Ser + Ser220Glu
Thr215Asn + Thr217Gln
Ser220Glu + Leu221Pro
Gly136Ser + Trp208Phe
Thr195Asp + Tyr210Gln
Leu104Gln + Ala219Asp
Gly 69Pro + Leu221Pro
Gly 69Asn + Ala204Gly
Gly135Glu + Ala219Asn
Gly136Asn + Ser220Glu
Gly136Ser + Trp208Val
Gly139Asp + Asn140Gln
Trp208Cys + Tyr210Asn
Gly165Ser + Ser220Asp
Gly110Ser + Trp208Thr
Ala114Asp + Gly162Asn
Ser192Asp + Leu221Cys
Val103Ser + Gly135Glu
Asn140Glu + Trp208Ala
Thr113Asp + Leu221Ser
Ser109Asp + Gly110Ser
Ser109Glu + Thr113Gln
Thr 73Gly + Gly136Asp
Ala164His + Leu221Asn
Gly 67Pro + Va1103His
Ala114Asn + Thr212Gln
Asn140Asp + Gly223Pro
Gly139Gln + Pro214Asn
Asp105Glu + Thr195Gly
Gly135Pro + Ser207Glu
Leu104Glu + Ala114Pro
Asn 66Glu + Gly 69Pro
Val115Cys + Ser207Glu
Asn 68Glu + Leu221Ala
Asn 66Ser + Gly 69Asp
Ser109Glu + Phe193Pro
Trp208Glu + Thr212Pro
Gly136Gln + Trp208Cys
Ser 70Asp + Leu221His
Ser 70Glu + Phe193Ser
Thr217Asn + Ser222Glu
Tyr213Thr + Tyr218Gly
Trp208Ser + Leu221Cys
Asn163Asp + Leu221Ser
Asn 66Gln + Gly223Pro
Gly139Asn + Ser220Asp
Thr 73Ser + Pro214Asp
Ser 70Asp + Leu221Ile
Gly165Gln + Ser220Asp
Asn166Asp + Thr217Asn
Asp105Glu + Thr111Pro
Asn140Asp + Trp208Phe
Asn166Glu + Pro214Asn
Trp208Ala + Thr217Ser
Gly108Ser + Gly110Glu
Val138Asn + Asn170Asp
Gly110Glu + Thr224Gln
Trp208Met + Ser220Asp
Asn 68Glu + Val115Ser
Asn170Glu + Tyr210Gly
Gly110Asn + Ser192Glu
Trp208Gln + Ser220Glu
Asn140Gln + Pro214Gln
Thr217Ser + Ser220Glu
Ser141Glu + Ala168Thr
Gly162Glu + Tyr210His
Leu104Gly + Thr224Asp
Trp112Pro + Ser191Asp
Trp208Thr + Tyr210Glu
Gly108Gln + Thr111Asp
Leu134Val + Thr217Pro
Asn170Asp + Tyr210His
Val115Ser + Ser220Glu
Gly 69Pro + Ser 70Asp
Thr 73Gly + Tyr210Glu
Gly 67Asp + Gly108Gln
Gly 69Ser + Gly110Asp
Tyr210Thr + Ser220Glu
Trp208Phe + Leu221Met
Gly136Gln + Leu221Asp
Thr113Ser + Trp208Val
Tyr171Leu + Tyr210Thr
Leu134Asn + Thr167Gln
Asn140Ser + Tyr210Asp
Asn 66Gln + Gly 67Glu
Leu134Cys + Pro214Asn
Gly136Ser + Leu221Ala
Thr111Pro + Trp208Val
Thr113Asp + Tyr171Gly
Trp208Ile + Ser220Glu
Pro214Ser + Thr224Glu
Gly165Pro + Ser220Glu
Thr137Gln + Tyr171Glu
TrP208Glu + Pro214Gly
Ser216Asp + Leu221Met
Gly136Ser + Thr217Gln
Ser141Glu + Tyr210Leu
Trp208Thr + Gly223Ser
Asn 66Ser + Asn170Gln
Asn 66Gln + Asn170Glu
Pro169Glu + Tyr210Thr
Tyr171Leu + Leu221Asp
Gly139Glu + Leu221Pro
Thr 73Pro + Leu134Gly
Tyr210Glu + Leu221Ala
Gly139Ser + Tyr210Gly
Asn163Asp + Ala164Ser
Asn163Gln + Thr217Asp
Asn140Asp + Tyr218Ser
Gly108Ser + Ala164Gln
Val138Ser + Trp208Leu
Thr217Ser + Thr224Asp
Ser109Asp + Tyr218Ala
Asn 66Glu + Phe193Val
Asn140Asp + Ala204Gly
Val138Ser + Ser220Asp
Gly108Asn + Tyr210Thr
Gly139Asn + Tyr171Pro
Thr113Pro + Trp208Thr
Ser141Glu + Leu221Gly
Asn106Glu + Thr167Gly
Trp112Ser + Ala219Ser
Asp105Glu + Asn166Gln
Ala114Pro + Tyr171Asn
Thr217Gln + Ser220Asp
Thr113Gly + Tyr210Asp
Tyr171Cys + Tyr210Glu
Asn166Asp + Leu221Val
Ala114His + Ser191Asp
Gly 67Glu + Thr217Asn
Asn 66Glu + Thr215Gln
Thr111Asn + Ser220Glu
Trp208Gln + Leu221Ser
Gly 69Gln + Ala114Thr
Asn163Asp + Leu221Ala
Pro214Gly + Leu221Ile
Thr217Gly + Ser220Asp
Ala219Thr + Ser220Asp
Tyr210Cys + Ser220Glu
Val138Asp + Gly223Pro
Thr195Asn + Leu221Gly
Leu104Thr + Thr215Ser
Gly 69Gln + Leu134Thr
Gly165Pro + Leu221Gly
Thr167Ser + Thr217Glu
Thr212Pro + Thr217Glu
Asn166Ser + Tyr218Asp
Gly108Glu + Tyr171Gln
Gly 67Asn + Tyr210Ile
Val115Cys + Pro214Gly
Thr137Asp + Tyr210Val
Leu104Met + Trp208Gly
Leu134Ala + Ser192Asp
Trp112Gln + Ala219Gln
Gly108Glu + Val115His
Thr113Asn + Gly139Pro
Trp208Gln + Gly223Asn
Ser207Glu + Trp208Gln
Asn 66Ser + Tyr210Asn
Ser207Glu + Tyr210Pro
Val103Ala + Thr215Glu
Val103Asn + Tyr210Ala
Asn 66Ser + Trp208Phe
Thr215Asn + Ala219Thr
Gly136Asn + Gly139Asn
Tyr171Thr + Ser216Glu
Leu104Glu + Tyr210Asn
Ser109Glu + Thr217Asn
Leu134Ile + Asn166Ser
Tyr171Gly + Thr217Gln
Val115Cys + Thr224Asp
Pro169Ser + Thr215Asp
Gly 72Gln + Gly135Asn
Tyr210Thr + Ser220Asp
Asn 68Glu + Thr113Ser
Asn106Gln + Thr113Asp
Ser109Glu + Trp208Asn
Leu134Gln + Thr137Glu
Ala114Thr + Asn170Glu
Ala219Pro + Ser220Glu
Tyr171Val + Trp208Pro
Gly139Ser + Tyr213Ser
Ser107Asp + Thr113Asn
Thr167Gly + Leu221Met
Tyr171Gly + Ser207Glu
Gly 67Ser + Thr217Ser
Val115Gly + Thr217Ser
Asn 66Ser + Trp208Ile
Ser191Glu + Trp208Cys
Thr137Asp + Trp208Ser
Leu221Gly + Ser222Glu
Ser216Glu + Leu221Thr
Gly162Pro + Ser207Glu
Thr217Asp + Ala219Thr
Leu104Cys + Ser207Glu
Gly 69Gln + Ser220Glu
Gly 69Gln + Val138Asp
Pro169Gly + Tyr210Leu
Thr 73Asp + Gly110Ser
Thr215Gly + Thr217Ser
Gly 69Ser + Gly 72Asn
Ser191Glu + Thr217Asn
Gly135Ser + Tyr171Ser
Thr111Asn + Phe193Leu
Trp112Leu + Ser207Asp
Leu104Glu + Trp208Ala
Leu221Ile + Thr224Asp
Gly136Glu + Gly165Asn
Tyr210Glu + Thr217Pro
Trp112Phe + Pro214Asp
Gly110Gln + Trp112Met
Asn 68Ser + Trp208Asp
Gly 69Ser + Leu104Cys
Thr137Glu + Thr215Pro
Asn166Gln + Thr217Glu
Tyr210Thr + Thr212Ser
Leu134His + Trp208Asp
Ser141Glu + Tyr210Val
Ser191Glu + Tyr210Leu
Gly139Pro + Ser207Asp
Gly162Ser + Tyr171Met
Thr 73Gln + Val103Ala
Tyr171Val + Phe193Asp
Leu221Thr + Ser222Glu
Gly 69Asp + Ala114Gln
Gly108Glu + Trp208Met
Gly 72Ser + Tyr210Gln
Thr137Asn + Trp208Asp
Asn140Asp + Phe193Thr
Ser192Glu + Trp208Ala
Asn170Glu + Pro205Ser
Tyr210Ala + Tyr213Ser
Tyr171Gln + Tyr218Ile
Asn 66Asp + Leu221Cys
Asn163Gln + Gly223Asn
Val103Thr + Leu134Ser
Thr167Ser + Asn170Asp
Ser 70Glu + Gly162Ser
Tyr171Gln + Ser192Glu
Tyr210Val + Gly223Ser
Thr137Glu + Leu221Pro
Gly 69Asn + Thr217Asp
Pro205Ser + Tyr218Glu
Tyr210Met + Leu221Asn
Thr215Asp + Thr217Pro
Leu134Val + Gly136Glu
Thr 73Pro + Leu221Glu
Tyr213Val + Ser220Glu
Thr 73Ser + Ser107Glu
Trp208Ser + Leu221Pro
Thr113Asp + Leu221His
Ala114Thr + Thr217Asp
Ala168Ser + Tyr218Glu
Trp208Asp + Leu221Asn
Thr137Asp + Trp208Ile
Gly135Gln + Ser191Glu
Val103Glu + Trp208Gly
Asn140Asp + Leu221His
Ser192Asp + Tyr210Cys
Gly108Asn + Tyr210His
Asp105Glu + Trp208Asn
Val103Pro + Tyr210Pro
Thr 73Gln + Trp112Tyr
Leu134Cys + Asn170Ser
Asn166Glu + Tyr210Cys
Asn106Ser + Leu221Met
Ser109Glu + Leu221Cys
Ser107Asp + Leu221Ala
Ala114Ser + Leu221Asn
Gly162Asn + Leu221Val
...
Table 33
Polycyclic three mutant
Leu104Gly + Tyr210Pro + Thr217Glu
Asn 66Gln + Gly 67Ser + Gly 69Ser
Val103Gln + Trp112Cys + Gly223Asp
Ala164Glu + Trp208Gln + Thr217Gly
Leu134Ile + Trp208Gln + Ser220Glu
Asn 66Asp + Leu104Gly + Ala219Gly
Leu104Ala + Thr111Gln + Val115Ala
Gly 69Ser + Ser109Asp + Tyr210Pro
Gly139Asn + Thr167Asn + Thr217Ser
Gly108Glu + Ala164Gly + Gly165Gln
Leu104His + Thr167Pro + Ser220Asp
Gly 69Glu + Asn106Gln + Trp208His
Trp112Cys + Thr113Pro + Trp208Asp
Gly110Ser + Ser207Glu + Thr212Ser
Ala168His + Trp208Tyr + Ser220Glu
Tyr171Asn + Thr217Asp + Leu221Met
Ser 70Asp + Thr137Asn + Thr217Pro
Thr167Glu + Ala168Thr + Tyr210Pro
Ser 70Glu + Gly136Pro + Leu221Ala
Gly 67Ser + Thr195Ser + Ser222Asp
Pro169Ser + Trp208Pro + Thr215Gly
Thr 73Gly + Leu104Gly + Tyr171Glu
Gly 72Gln + Tyr210Ile + Leu221Gly
Leu104Gln + Thr137Gly + Tyr210Ala
Tyr213Ser + Thr217Gly + Gly223Glu
Gly 72Asn + Thr195Asp + Ala219Asn
Thr137Asp + Val138Pro + Tyr210Ala
Ser109Glu + Val115Met + Trp208Cys
Gly139Asn + Ser220Glu + Leu221Asn
Trp112Ala + Gly135Glu + Leu221Gly
Thr113Asn + Thr195Asn + Thr217Ser
Ala164His + Ser220Asp + Leu221His
Asn 66Asp + Thr 73Ser + Thr113Gln
Gly135Ser + Thr167Gln + Thr217Gly
Tyr171Asp + Trp208His + Thr217Asn
Gly108Asn + Trp208Leu + Tyr210Val
Trp112Cys + Ser220Glu + Leu221Asn
Val103Met + Ala168His + Ser191Asp
Pro214Ser + Thr217Gln + Ser220Glu
Thr215Asn + Ser220Glu + Leu221Pro
Gly136Ser + Trp208Phe + Tyr210Gln
Gly 69Pro + Ala219Asp + Leu221Pro
Gly 69Asn + Ala204Gly + Ser220Asp
Gly136Ser + Gly139Asp + Trp208Val
Asn140Gln + Trp208Cys + Tyr210Asn
Gly110Ser + Gly165Ser + Trp208Thr
Val103Ser + Gly135Glu + Leu221Cys
Asn140Glu + Trp208Ala + Leu221Ser
Gly 67Pro + Val103His + Ala164His
Asn140Asp + Thr212Gln + Gly223Pro
Gly139Gln + Thr195Gly + Pro214Asn
Gly 69Pro + Leu104Glu + Ala114Pro
Phe193Pro + Trp208Glu + Thr212Pro
Gly136Gln + Trp208Cys + Leu221His
Ser 70Asp + Thr 73Gly + Phe193Ser
Tyr213Thr + Tyr218Gly + Gly223Asp
Thr195Glu + Trp208Ser + Leu221Cys
Asn163Asp + Leu221Ser + Gly223Pro
Asn 66Gln + Gly139Asn + Ser220Asp
Thr 73Ser + Pro214Asp + Leu221Ile
Thr111Pro + Asn140Asp + Trp208Phe
Asn166Glu + Pro214Asn + Thr217Ser
Gly108Ser + Gly110Glu + Trp208Ala
Leu134Asp + Gly165Asn + Tyr210Thr
Phe193Thr + Thr217Gln + Ser220Asp
Gly 67Pro + Trp112Gln + Ser192Asp
Tyr210Ile + Thr217Gln + Ser222Asp
Val103Ser + Leu104Ile + Ala164Asn
Ala114Asp + Thr167Gly + Thr217Asn
Thr111Asp + Thr195Gly + Tyr210Leu
Tyr210Thr + Ser220Glu + Leu221Met
Gly136Gln + Trp208Phe + Leu221Asp
Thr113Ser + Trp208Val + Tyr210Thr
Leu134Asn + Asn140Ser + Thr167Gln
Gly136Ser + Trp208Val + Leu221Ala
Gly165Pro + Pro214Ser + Ser220Glu
Gly136Ser + Tyr210Leu + Thr217Gln
Ser141Glu + Trp208Thr + Gly223Ser
Asn 66Ser + Thr113Pro + Asn170Glu
Thr 73Pro + Tyr210Thr + Ser216Glu
Thr 73Pro + Tyr210Glu + Leu221Ala
Gly139Ser + Ala164Ser + Tyr210Gly
Gly108Ser + Val138Ser + Ala164Gln
Trp208Leu + Thr217Ser + Thr224Asp
Asn 66Glu + Phe193Val + Tyr218Ala
Gly108Asn + Tyr171Pro + Tyr210Thr
Thr113Pro + Gly139Asn + Trp208Thr
Asp105Glu + Asn166Gln + Tyr171Asn
Ala114Pro + Thr217Gln + Ser220Asp
Gly 67Glu + Ala114His + Thr217Asn
Ser141Glu + Trp208Gln + Leu221Ser
Gly 69Gln + Ala114Thr + Asn170Asp
Asn163Asp + Ala219Thr + Leu221Ala
Ser 70Asp + Thr217Gly + Ala219Thr
Thr195Asn + Leu221Gly + Gly223Pro
Gly 69Gln + Leu104Thr + Leu134Thr
Gly139Asp + Gly165Pro + Leu221Gly
Gly 67Asn + Gly108Glu + Tyr210Ile
Val115Cys + Tyr210Val + Pro214Gly
Leu104Met + Thr137Asp + Trp208Gly
Trp112Gln + Leu134Ala + Ser192Asp
Gly108Glu + Val115His + Ala219Gln
Thr113Asn + Gly139Pro + Thr167Asp
Thr137Asp + Trp208Gln + Gly223Asn
Ser207Glu + Trp208Gln + Tyr210Asn
Asn 66Ser + Ser207Glu + Tyr210Pro
Val103Asn + Tyr210Ala + Thr215Glu
Asn 66Ser + Trp208Phe + Ala219Thr
Gly136Asn + Gly139Asn + Thr215Asn
Ser109Glu + Asn166Ser + Thr217Asn
Leu134Ile + Tyr171Gly + Thr217Gln
Gly 72Gln + Gly110Asp + Gly135Asn
Asn 68Glu + Asn106Gln + Thr113Ser
Ala114Thr + Leu134Gln + Thr137Glu
Ser107Asp + Gly139Ser + Tyr213Ser
Thr113Asn + Thr167Gly + Leu221Met
Gly 67Ser + Ser207Glu + Thr217Ser
Asn 66Ser + Trp208Ile + Thr217Ser
Trp208Ser + Leu221Gly + Ser222Glu
Gly162Pro + Ser216Glu + Leu221Thr
Leu104Cys + Asn106Gln + Ser207Glu
Gly 69Gln + Pro169Gly + Tyr210Leu
Thr 73Asp + Gly110Ser + Thr217Ser
Gly 69Ser + Gly 72Asn + Thr215Gly
Gly135Ser + Tyr171Ser + Ser191Glu
Thr111Asn + Phe193Leu + Thr217Glu
Trp208Ala + Leu221Ile + Thr224Asp
Trp112Phe + Pro214Asp + Thr217Pro
Asn 68Ser + Gly110Gln + Trp112Met
Gly 69Ser + Leu104Cys + Trp208Asp
Thr137Glu + Asn166Gln + Thr215Pro
Gly108Glu + Tyr210Thr + Thr212Ser
Thr 73Gln + Gly162Ser + Tyr171Met
Tyr171Val + Phe193Asp + Leu221Thr
Gly 72Ser + Gly108Glu + Trp208Met
Thr137Asn + Trp208Asp + Tyr210Gln
Asn140Asp + Phe193Thr + Trp208Ala
Gly 69Glu + Tyr210Ala + Tyr213Ser
Asn 66Asp + Tyr218Ile + Leu221Cys
Val103Thr + Leu134Ser + Asn163Gln
Tyr171Gln + Ser192Glu + Gly223Ser
Gly 69Asn + Thr137Glu + Leu221Pro
Pro205Ser + Tyr218Glu + Leu221Asn
Tyr210Met + Thr215Asp + Thr217Pro
Thr 73Pro + Leu134Val + Gly136Glu
Thr 73Ser + Ser107Glu + Trp208Ser
Gly162Gln + Ser220Asp + Leu221Pro
Val103Glu + Gly135Gln + Trp208Gly
Asn140Asp + Tyr210Cys + Leu221His
Gly108Asn + Ser192Asp + Tyr210His
Asp105Glu + Trp208Asn + Tyr210Pro
Thr 73Gln + Val103Pro + Trp112Tyr
Leu134Cys + Asn170Ser + Tyr210Cys
Asn106Ser + Ser109Glu + Leu221Cys
Ser107Asp + Ala114Ser + Leu221Ala
Gly 69Asn + Gly162Asn + Leu221Asn
Gly 67Ser + Gly135Asp + Gly162Asn
Val115Gly + Leu134Ser + Ala164Gln
Asn 66Glu + Leu104Asn + Ala168Gly
Gly 69Ser + Asn166Glu + Tyr218Asn
Thr113Asp + Ala204Ser + Tyr218Ser
Asn166Gln + Trp208Thr + Thr217Asp
Gly108Glu + Thr217Ser + Tyr218Gly
Asn106Asp + Trp208Met + Thr217Gln
Gly 69Glu + Tyr171Val + Trp208His
Gly139Asn + Pro169Gly + Trp208Asn
Val115Ala + Thr215Gln + Leu221Glu
Thr111Pro + Pro169Gln + Ala219Glu
Thr 73Glu + Thr137Asn + Trp208His
Asn 66Asp + Asn106Ser + Leu221Thr
Gly 67Pro + Gly 69Ser + Thr224Ser
Val115His + Ser191Asp + Tyr218Val
Thr137Glu + Thr195Asn + Trp208Gly
Leu134Glu + Trp208Ser + Leu221Ser
Val103Ser + Trp208Glu + Thr217Asn
Gly139Asn + Phe193Pro + Leu221Cys
Asn106Gln + Ala164Pro + Asn166Asp
Asp105Glu + Val138Ser + Thr217Pro
Gly135Pro + Tyr171Thr + Ser222Glu
Ser216Asp + Thr217Asn + Thr224Gly
Ala114Gly + Asn140Gln + Tyr218Asp
Ser107Asp + Pro214Gly + Leu221Ser
Asp105Glu + Asn170Ser + Thr195Pro
Ser 70Glu + Tyr171Leu + Pro214Ser
Gly 67Asp + Leu104Thr + Gly223Asn
Gly108Asp + Ala114Asn + Tyr210Cys
Gly110Asn + Pro214Gly + Ser220Asp
Gly 69Asn + Pro169Gln + Ser220Glu
Gly162Glu + Trp208Ala + Thr217Asn
Trp112Tyr + Val115Pro + Ser220Glu
Trp208Gly + Tyr210Ile + Pro214Asp
Leu134Asn + Pro169Ser + Leu221Asp
Thr113Ser + Trp208Leu + Leu221Glu
Asn166Ser + Tyr218Ile + Ser220Glu
Trp112Pro + Phe193His + Pro214Asp
Leu104Glu + Val115Ser + Ala164Ser
Gly 69Pro + Pro169Asp + Leu221His
Gly108Gln + Val138Ser + Ser220Glu
Gly110Asn + Thr137Gln + Ser220Glu
Ala164Thr + Asn166Ser + Tyr210Asp
Trp112Pro + Val115Pro + Pro214Glu
Val115Glu + Gly139Asn + Tyr210Gln
Gly 69Ser + Thr 73Ser + Tyr210Pro
Ala114Ser + Ser207Asp + Thr224Pro
Thr 73Pro + Asn166Glu + Thr212Gly
Gly 72Gln + Gly110Asp + Leu221His
Tyr210Cys + Pro214Asn + Tyr218Asp
Gly 69Asn + Gly136Pro + Asn166Ser
Thr 73Gly + Gly108Ser + Ser220Glu
Thr 73Gly + Pro205Ser + Thr224Ser
Val103Met + Ala164Asp + Leu221Met
Thr111Asn + Thr167Glu + Phe193Met
Thr 73Asp + Tyr210Asn + Thr217Gln
Asn 66Glu + Thr 73Gly + Leu221Gln
Thr113Asp + Asn166Ser + Thr167Pro
Asn 66Gln + Tyr171Gly + Tyr210Pro
Asn 68Ser + Gly 69Pro + Asn170Gln
Asn 68Ser + Val115Glu + Tyr210Asn
Thr113Gln + Ser191Asp + Leu221His
Thr167Pro + Trp208Val + Tyr210Leu
Gly162Glu + Trp208Ala + Thr217Pro
Leu104Met + Ser207Asp + Thr212Gly
Thr137Gln + Asn163Asp + Pro205Gln
Val115Thr + Thr217Gln + Ser220Asp
Ser 70Asp + Val138Ser + Tyr210Val
Pro214Gly + Leu221Ile + Thr224Asp
Leu134Val + Gly165Gln + Trp208Thr
Ser109Asp + Ala114Asn + Tyr210Ser
Asn 66Ser + Val115Asn + Trp208Gln
Thr 73Pro + Phe193Glu + Gly206Gln
Leu134Ser + Leu221Pro + Ser222Asp
Val115Cys + Ala164Glu + Asn170Gln
Ala164Asn + Trp208Cys + Thr217Glu
Asn 66Glu + Ala168Pro + Thr215Pro
Gly135Ser + Ser207Asp + Thr217Gln
Asn140Gln + Thr167Asp + Trp208Met
Gly165Gln + Trp208Thr + Leu221Asn
Thr 73Pro + Asn106Glu + Leu221Cys
Thr113Ser + Leu221Ile + Gly223Asp
Asn 66Asp + Gly136Gln + Gly162Gln
Ser191Glu + Thr217Asn + Thr224Pro
Leu104Gln + Gly162Glu + Tyr210Gln
Trp112Gln + Asn163Asp + Thr217Gly
Leu134Pro + Thr217Asn + Leu221Glu
Gly165Pro + Tyr210Met + Thr217Glu
Ala164Gly + Ser191Glu + Trp208Cys
Val115Cys + Gly139Asn + Pro205Asn
Gly135Pro + Trp208Ala + Tyr210Pro
Pro169Asn + Thr195Glu + Tyr210His
Ser107Asp + Trp208Met + Tyr210Pro
Thr 73Gly + Ala164Gly + Tyr210Glu
Leu104Val + Pro205Gln + Leu221Asp
Thr111Gln + Ser141Asp + Leu221Asn
Trp112Cys + Thr167Gln + Thr217Pro
Val138Thr + Asn170Glu + Leu221Pro
Ser 70Asp + Leu134Ser + Thr224Asn
Thr137Asn + Ser207Asp + Tyr218Thr
Gly135Glu + Ala164Asn + Ala203Ser
Leu134Gly + Trp208Glu + Thr212Ser
Asn163Asp + Trp208Asn + Tyr210Thr
Val115Thr + Ser192Glu + Thr217Ser
Gly 72Pro + Ser109Asp + Tyr210Gln
Ser109Glu + Asn163Gln + Phe193Pro
Gly136Pro + Pro169Glu + Leu221Ser
Gly110Asn + Ser220Glu + Leu221Met
Trp112Gly + Tyr210Asp + Thr217Pro
Trp208Ser + Tyr210Ser + Leu221Pro
Trp112Met + Ser192Glu + Leu221Ala
Thr137Gly + Thr167Ser + Thr217Glu
Ser109Asp + Gly162Pro + Tyr210Ala
Ala114Thr + Gly162Asn + Ser191Glu
Thr195Asn + Tyr218Pro + Leu221Glu
Thr 73Glu + Ala164Gln + Pro214Ser
Asn 68Glu + Trp208Tyr + Thr217Asn
Gly165Pro + Thr212Ser + Ser220Glu
Gly 67Asn + Gly139Gln + Ala168Asp
Ser141Glu + Pro214Gln + Leu221Gln
Gly206Ser + Trp208Tyr + Thr215Gln
Leu134Pro + Gly162Asn + Phe193Ile
Trp112Ala + Thr217Asn + Ser220Asp
Thr111Gly + Gly139Glu + Thr212Asn
Ser107Glu + Tyr213Ala + Thr217Pro
Gly165Ser + Thr217Glu + Gly223Pro
Tyr210His + Thr217Asp + Leu221Ala
Trp208Cys + Thr217Asp + Tyr218Asn
Gly 69Gln + Val103Ala + Ser220Glu
Asn106Ser + Tyr210Gly + Gly223Ser
Trp208Cys + Tyr210Asn + Thr217Asp
Asn 66Gln + Gly139Gln + Thr217Gly
Thr 73Glu + Leu104Ile + Tyr210Ile
Thr113Ser + Pro169Asn + Thr217Ser
Tyr210Gly + Pro214Gly + Leu221Glu
Leu134Ile + Ala219Glu + Ser220Asp
Asn140Asp + Ser141Glu + Tyr218Ser
Tyr213Val + Ser220Glu + Leu221Glu
Tyr210Val + Ser220Glu + Leu221Asp
Ala164His + Ser220Glu + Leu221Glu
Tyr171His + Ser220Asp + Leu221Glu
Tyr210Ile + Ser220Glu + Leu221Asp
Trp112Leu + Ser220Asp + Leu221Glu
Gly136Pro + Ser191Asp + Ser192Glu
Ala168Ser + Thr217Asp + Tyr218Glu
Asn166Ser + Thr217Glu + Tyr218Asp
Gly162Asp + Asn163Glu + Leu221Met
Trp208Ser + Tyr210Glu + Ser220Asp
Ala114Thr + Gly165Asp + Phe193Glu
Ser207Glu + Thr217Asn + Ser222Glu
Asn140Ser + Trp208Glu + Ser220Asp
Trp208Asp + Leu221Asn + Ser222Glu
Gly139Gln + Trp208Glu + Leu221Asp
Asn 68Glu + Asp105Glu + Asn106Asp
Thr137Gln + Gly139Asp + Tyr171Glu
Trp208Asp + Tyr210Glu + Leu221Ala
Gly 69Pro + Asn166Glu + Ala168Glu
Tyr171Cys + Tyr210Glu + Leu221Asp
Thr137Glu + Pro169Asp + Asn170Ser
Gly162Glu + Tyr171Asp + Thr217Ser
Leu134Ile + Ser191Glu + Gly223Glu
Val115Pro + Ser207Glu + Ser220Asp
Gly139Pro + Ser207Asp + Ser220Glu
Ser 70Glu + Val103Pro + Asn106Asp
Gly 69Asp + Thr 73Asp + Tyr218Ile
Asn 66Asp + Trp208Gly + Pro214Glu
Asn 66Asp + Ser 70Glu + Gly136Ser
Asn163Asp + Ser191Asp + Ser207Glu
Asn 66Ser + Gly 69Asp + Ser109Glu
Gly 67Glu + Trp208Ile + Thr215Asp
Ser 70Glu + Tyr210Gln + Thr217Glu
Ser 70Glu + Gly135Pro + Thr217Glu
Val138Glu + Ser141Asp + Tyr210Gln
Val138Glu + Ser141Glu + Pro214Asn
Ser107Asp + Gly110Asp + Ala114Glu
Ser109Glu + Ala114Glu + Gly136Ser
Gly110Glu + Gly136Glu + Tyr210Gln
Gly135Ser + Tyr210Asp + Thr217Glu
Ser 70Glu + Pro169Asn + Leu221Asp
Val115Gly + Gly162Asp + Thr167Asp
Gly110Pro + Thr217Asp + Ser220Asp
Ala164His + Thr217Asp + Ser220Asp
Tyr210Cys + Thr217Asp + Ser220Asp
Val103Ser + Thr217Asp + Ser220Asp
Thr217Glu + Tyr218Val + Ser220Glu
Gly 69Ser + Thr217Glu + Ser220Glu
Tyr210Val + Thr217Asp + Ser220Glu
Gly 67Glu + Ser107Glu + Thr111Asn
Asn166Asp + Ser191Asp + Leu221Val
Leu134Asp + Phe193Glu + Gly223Asp
Asn 66Asp + Ser216Asp + Thr217Glu
Val103Glu + Asn106Glu + Thr113Glu
Ser 70Asp + Gly139Ser + Ser220Asp
Leu104Asp + Asp105Glu + Ser191Glu
Ala114Glu + Ser216Asp + Thr217Glu
Thr195Glu + Ser216Asp + Thr217Glu
Val115Glu + Ser220Asp + Leu221Glu
Ser109Asp + Ser220Asp + Leu221Glu
Thr215Glu + Ser216Asp + Ser220Asp
Ser192Asp + Phe193Glu + Thr217Asp
Gly165Asp + Tyr210Glu + Ser220Asp
Ser 70Glu + Asp105Glu + Tyr218Asp
Gly 69Glu + Ala168Glu + Thr195Glu
...
Table 34
Polycyclic four mutant
Asn 66Gln + Leu104Gly + Tyr210Pro + Thr217Glu
Gly 67Ser + Gly 69Ser + Val103Gln + Gly223Asp
Trp112Cys + Ala164Glu + Trp208Gln + Thr217Gly
Leu134Ile + Trp208Gln + Ala219Gly + Ser220Glu
Leu104Ala + Ser109Glu + Thr111Gln + Val115Ala
Gly108Glu + Ala164Gly + Gly165Gln + Thr167Pro
Gly 69Glu + Asn106Gln + Trp112Cys + Thr113Pro
Thr 73Asp + Leu134Ser + Thr137Asn + Thr217Pro
Gly 67Ser + Gly136Pro + Thr195Ser + Leu221Ala
Thr 73Gly + Leu104Gly + Trp208Pro + Thr215Gly
Gly110Glu + Gly136Pro + Phe193Met + Thr217Pro
Ala164Gln + Tyr171Ile + Phe193Ile + Thr224Gly
Gly136Pro + Ala164Thr + Ser207Asp + Trp208Leu
Gly108Gln + Trp112Pro + Trp208Thr + Tyr210Glu
Thr111Asp + Leu134Val + Tyr210His + Thr217Pro
Gly136Gln + Trp208Phe + Ala219Asp + Leu221Met
Thr113Ser + Tyr171Leu + Trp208Val + Tyr210Thr
Gly136Ser + Ser141Glu + Trp208Thr + Tyr210Leu
Asn 66Ser + Thr 73Pro + Thr113Pro + Asn170Glu
Thr 73Pro + Gly139Ser + Tyr210Glu + Leu221Ala
Gly108Ser + Val138Ser + Trp208Leu + Thr217Ser
Asn 68Ser + Gly110Gln + Trp112Met + Ser192Asp
Thr 73Gln + Val103Ala + Gly162Ser + Ala164Glu
Thr137Asn + Asn140Asp + Phe193Thr + Trp208Ala
Leu134Ser + Asn163Gln + Ser220Glu + Gly223Asn
Asn140Glu + Tyr171Gln + Tyr210Val + Gly223Ser
Thr 73Pro + Leu134Val + Gly136Glu + Thr217Pro
Ser107Glu + Gly162Gln + Trp208Ser + Leu221Pro
Gly108Asn + Gly162Asn + Ser192Asp + Tyr210Cys
Val103Pro + Ser109Glu + Trp208Asn + Tyr210Pro
Thr 73Gln + Trp112Tyr + Leu134Cys + Asn170Ser
Gly 69Asn + Gly162Asn + Asn166Ser + Leu221Asn
Gly 67Ser + Leu134Ser + Gly162Asn + Ala164Gln
Leu134Ile + Gly135Pro + Ala168Thr + Trp208Met
Trp112Ser + Ala168His + Thr217Ser + Leu221Ala
Gly110Ser + Thr111Gln + Thr215Ser + Ser222Asp
Thr111Pro + Thr137Asn + Pro169Gln + Ala219Glu
Thr 73Glu + Asn106Ser + Trp208His + Leu221Thr
Asn 66Asp + Gly 67Pro + Gly 69Ser + Thr224Ser
Leu104Cys + Val115His + Ser191Asp + Tyr218Val
Leu134Glu + Thr195Asn + Trp208Ser + Leu221Ser
Val103Ser + Gly139Asn + Thr217Asn + Leu221Cys
Asn106Gln + Ala164Pro + Asn166Asp + Phe193Pro
Asp105Glu + Gly135Pro + Val138Ser + Thr217Pro
Gly 67Asp + Thr113Asn + Ala114Asn + Tyr210Cys
Asn166Asp + Thr195Gly + Tyr210Gly + Thr224Gln
Trp112Pro + Asn166Ser + Phe193His + Tyr218Ile
Gly 69Pro + Leu104Glu + Val115Ser + Ala164Ser
Trp112Pro + Val115Glu + Gly139Asn + Tyr210Gln
Gly 69Ser + Thr 73Ser + Tyr210Pro + Thr224Pro
Gly 72Gln + Thr 73Pro + Gly110Asp + Leu221His
Thr111Asn + Gly136Pro + Tyr210Thr + Tyr218Asp
Gly108Asp + Gly136Asn + Asn166Ser + Leu221Thr
Val103Met + Pro205Ser + Leu221Met + Thr224Ser
Gly 69Asn + Thr 73Asp + Trp208Gln + Tyr210Leu
Thr 73Gly + Asn166Ser + Thr167Pro + Leu221Gln
Asn 66Gln + Thr113Asp + Tyr171Gly + Tyr210Pro
Gly162Glu + Thr167Pro + Trp208Val + Tyr210Leu
Ser207Asp + Trp208Ala + Thr212Gly + Thr217Pro
Leu104Met + Thr137Gln + Asn163Asp + Pro205Gln
Ser109Asp + Leu134Val + Gly165Gln + Trp208Thr
Ala114Asn + Val115Asn + Trp208Gln + Tyr210Ser
Asn 66Glu + Ala164Asn + Trp208Cys + Thr215Pro
Gly135Ser + Ala168Pro + Ser207Asp + Thr217Gln
Thr167Asp + Trp208Met + Thr217Gln + Leu221Asn
Thr 73Pro + Asn106Glu + Thr113Ser + Leu221Cys
Gly162Gln + Ser191Glu + Thr217Asn + Thr224Pro
Gly 69Gln + Leu104Gln + Gly162Glu + Tyr210Gln
Leu104Gln + Tyr171Pro + Thr217Gly + Leu221Glu
Gly110Glu + Phe193Asn + Trp208Cys + Gly223Pro
Ala164Gly + Ser191Glu + Pro205Asn + Trp208Cys
Gly135Pro + Ser207Glu + Trp208Ala + Tyr210Cys
Thr 73Glu + Leu104Val + Pro205Gln + Leu221Cys
Trp112Cys + Val138Thr + Thr167Gln + Thr217Pro
Ser109Asp + Ala164His + Gly223Pro + Thr224Asn
Asn 68Gln + Tyr210Pro + Thr212Ser + Ser220Asp
Leu134Gly + Trp208Glu + Tyr210Met + Thr212Ser
Asn163Asp + Asn170Gln + Trp208Asn + Tyr210Thr
Trp112Gly + Trp208Ser + Tyr210Asp + Thr217Pro
Trp112Met + Ser192Glu + Trp208Ser + Tyr210Val
Trp112Leu + Ser220Asp + Leu221Ala + Thr224Asn
Leu104Met + Thr111Asp + Ala164Gln + Pro214Ser
Gly139Gln + Gly165Pro + Thr212Ser + Ser220Glu
Thr113Asp + Leu134His + Trp208Ile + Leu221Ala
Asp105Glu + Pro214Gln + Thr215Gln + Leu221Gln
Leu134Pro + Gly162Asn + Gly206Ser + Trp208Tyr
Trp112Ala + Phe193Ile + Thr217Asn + Ser220Asp
Ser107Glu + Thr212Asn + Tyr213Ala + Thr217Pro
Gly 67Gln + Gly 69Gln + Thr113Asn + Ser220Glu
Asn 66Gln + Trp208Cys + Tyr210Asn + Thr217Asp
Thr 73Glu + Leu104Ile + Gly139Gln + Thr217Gly
Thr113Ser + Pro169Asn + Tyr210Ile + Thr217Ser
Leu134Pro + Thr167Gln + Tyr210Met + Ser220Asp
Thr 73Glu + Asn166Gln + Tyr171His + Leu221Ala
Val138Met + Asn170Gln + Thr217Asn + Ala219His
Gly136Gln + Ala219Ser + Ser220Asp + Thr224Gln
Gly 69Asn + Asn166Gln + Tyr210Glu + Thr217Gly
Thr 73Ser + Gly165Gln + Thr212Pro + Ser222Glu
Thr137Pro + Asn140Gln + Tyr171Gly + Ser220Glu
Tyr210Pro + Tyr213Ile + Ser220Asp + Leu221Pro
Val103Asp + Asn106Ser + Phe193His + Thr217Gly
Asn 68Asp + Thr113Asn + Val138Ala + Trp208His
Asp105Glu + Leu134Met + Gly165Ser + Leu221Gln
Asn 68Gln + Trp208Thr + Thr217Ser + Ser220Asp
Tyr171Asn + Thr195Asn + Tyr210Asn + Tyr218Asn
Asn 66Ser + Pro169Ser + Tyr210Cys + Gly223Glu
Ala114Gln + Phe193Glu + Tyr210Gly + Thr224Pro
Asn 66Ser + Gly136Ser + Ala164Asp + Ala168Gln
Leu104Gly + Gly162Pro + Ser192Asp + Leu221Asn
Gly108Asp + Gly162Pro + Trp208Thr + Gly223Asn
Asn 66Glu + Thr113Gly + Ala164Pro + Gly223Pro
Gly110Pro + Trp112Ala + Ser216Glu + Leu221His
Val115Met + Pro169Ser + Trp208His + Tyr210Asp
Leu104Ser + Ser109Asp + Gly110Pro + Thr195Gly
Leu104Asn + Thr137Glu + Trp208Ser + Leu221Val
Asn106Gln + Ala114Asp + Tyr171Thr + Leu221Pro
Pro205Asn + Tyr210Asn + Thr217Gly + Tyr218Leu
Leu104Pro + Asn106Ser + Thr137Asp + Thr217Pro
Gly110Ser + Thr137Gln + Asn170Glu + Thr217Asn
Thr113Gly + Phe193Met + Trp208His + Tyr213Ile
Asn166Gln + Ser207Asp + Thr217Ser + Tyr218Met
Gly162Asp + Phe193Pro + Trp208Tyr + Thr217Gln
Gly 69Ser + Ser107Glu + Trp208Met + Tyr210Leu
Val103Asp + Thr167Pro + Ile209Val + Tyr210Gln
Thr111Asn + Asn170Ser + Trp208Tyr + Thr212Gly
Ser107Glu + Thr137Pro + Gly162Ser + Trp208Cys
Val103Thr + Ala164Thr + Ala168Glu + Thr217Ser
Gly139Pro + Tyr210Asn + Leu221Pro + Thr224Pro
Leu134Ser + Ser141Glu + Tyr210Ala + Thr217Gln
Val103Asn + Leu134Ala + Tyr218Met + Thr224Asn
Asn 66Asp + Gly135Gln + Asn163Ser + Leu221Val
Gly 69Glu + Val115Pro + Thr137Pro + Trp208Ile
Gly 69Pro + Gly165Pro + Tyr210Ser + Leu221Ile
Asn 66Gln + Gly110Glu + Trp112Gly + Trp208Pro
Trp112Ala + Ala114Pro + Gly135Ser + Asn163Asp
Gly 67Asn + Ser207Glu + Tyr210Thr + Thr217Pro
Asn166Asp + Thr167Pro + Ile209His + Tyr210Val
Thr 73Ser + Asn106Gln + Tyr171Glu + Thr217Asn
Val115Glu + Tyr210Ser + Thr217Gln + Ala219Gly
Leu104Pro + Thr195Gln + Trp208Tyr + Ser222Asp
Ser141Asp + Ala204Gln + Trp208Val + Tyr210Leu
Gly 67Ser + Gly 69Glu + Val103Gly + Tyr210Gln
Tyr171Met + Phe193Leu + Thr215Asp + Thr217Gln
Asn 68Gln + Asp105Glu + Trp208Phe + Leu221Ala
Leu104Asn + Val115Gln + Leu134Gln + Pro214Glu
Gly165Ser + Ser191Asp + Pro214Gly + Leu221Thr
Gly 67Ser + Asn 68Gln + Tyr210Val + Ser220Asp
Ser109Asp + Val138Gly + Trp208Ser + Thr217Pro
Thr111Gly + Gly136Pro + Ser141Asp + Leu221Ile
Trp112Asn + Gly162Ser + Ile209Cys + Thr224Gln
Val115Ala + Pro169Glu + Tyr210Val + Leu221Cys
Gly135Ser + Tyr210Leu + Thr217Glu + Leu221Pro
Asn 66Gln + Ser109Asp + Gly110Gln + Tyr218Thr
Thr 73Gly + Trp208Ile + Thr217Glu + Leu221Asn
Leu134Ser + Trp208His + Tyr210Leu + Ser220Glu
Gly135Pro + Thr137Gln + Ala219Ser + Leu221Gln
Asn 68Gln + Asn106Glu + Pro169Gln + Thr215Gln
Val138Gln + Gly165Glu + Tyr218Leu + Leu221Cys
Phe193Gln + Ser207Asp + Trp208Cys + Thr217Gln
Gly 67Asn + Gly165Asn + Phe193Tyr + Pro205Ser
Asn 66Ser + Ala168Ser + Tyr210Cys + Thr217Asp
Pro214Gly + Ser216Asp + Thr217Gln + Leu221His
Asn 66Gln + Val115Gln + Asn166Asp + Tyr218Met
Thr111Glu + Gly165Ser + Ala219His + Leu221Thr
Ser141Asp + Asn163Ser + Phe193Tyr + Ala204Ser
Gly108Pro + Asn163Ser + Gly165Asp + Tyr213Ser
Trp208His + Tyr210Thr + Tyr218Gln + Ser220Asp
Gly 69Glu + Ala164Pro + Trp208Val + Thr224Ser
Ser109Asp + Ala203Pro + Trp208His + Thr217Ser
Thr 73Asp + Tyr171Cys + Tyr210Pro + Leu221Pro
Gly162Pro + Tyr218Val + Ala219Thr + Ser220Glu
Asn170Gln + Ser192Glu + Trp208Pro + Tyr210Gly
Thr113Ser + Thr137Gln + Phe193Ser + Pro205Ser
Trp112Pro + Thr137Gly + Ser220Asp + Leu221Asn
Gly162Glu + Ala164Ser + Ala168His + Pro214Asn
Ala114Pro + Leu134Glu + Asn140Ser + Phe193Ile
Ala164Gln + Ala168Glu + Trp208Asn + Tyr210Leu
Val103Pro + Gly139Pro + Asn163Asp + Gly165Gln
Gly162Ser + Trp208Glu + Tyr210Ser + Leu221Gln
Serl41Asp + Tyr171His + Trp208Ala + Leu221Met
Asn 66Ser + Gly139Gln + Asn163Gln + Tyr210Thr
Leu134Asp + Gly136Ser + Asn163Gln + Trp208Val
Ser191Asp + Phe193Leu + Pro214Gln + Thr217Ser
Gly 67Asn + Gly108Asp + Thr195Asn + Thr215Pro
Ala114Thr + Asn140GIu + Asn166Ser + Ala203Pro
Ser191Glu + Ala203Gly + Trp208Asn + Tyr210Ala
Asn140Asp + Ser141Glu + Ala164Gln + Tyr218Ser
Thr 73Ser + Tyr213Val + Ser220Glu + Leu221Glu
Phe193Met + Thr215Gln + Ser220Glu + Leu221Glu
Thr113Ser + Trp208Leu + Ser220Glu + Leu221Glu
Thr 73Pro + Val115Ala + Ser192Asp + Phe193Glu
Ala114Asn + Trp208Pro + Tyr210Glu + Ser220Glu
Trp208Cys + Tyr210Glu + Ala219Asn + Ser220Asp
Ala114Pro + Gly139Pro + Tyr210Asp + Ser220Glu
Tyr210Glu + Thr217Gln + Tyr218Gln + Ser220Glu
Asn140Ser + Trp208Glu + Ser220Asp + Leu221Asp
Val103Pro + Trp208Glu + Tyr210Ser + Ser220Glu
Thr 73Gln + Ser107Asp + Ser109Glu + Asn163Gln
Gly 67Gln + Ser107Asp + Ser109Glu + Leu221Cys
Asp105Glu + Asn106Ser + Ser109Glu + Thr217Pro
Leu104Glu + Asp105Glu + Ser107Asp + Leu221Ser
Gly206Pro + Pro214Asp + Thr217Glu + Leu221Asn
Ser207Asp + Trp208Glu + Ser220Asp + Leu221Ser
Gly135Asp + Gly162Glu + Tyr171Asp + Thr217Ser
Gly 69Glu + Leu104Asp + Asp105Glu + Tyr210Ala
Ala168Asn + Ser220Asp + Leu221Pro + Ser222Asp
Phe193Gln + Ser207Glu + Thr217Ser + Leu221Glu
Gly110Gln + Gly165Gln + Ser222Asp + Thr224Asp
Asn106Glu + Ser109Asp + Phe193Ile + Trp208Leu
Gly110Asn + Thr137Glu + Pro169Asp + Asn170Ser
Gly136Glu + Gly162Glu + Trp208Ala + Thr217Asn
Leu134Ile + Ser191Glu + Leu221His + Gly223Glu
Gly139Pro + Tyr171Met + Ser207Asp + Ser220Glu
Val103Pro + Thr111Gly + Ser207Asp + Ser220Asp
Gly108Asn + Thr195Gly + Ser207Asp + Ser220Asp
Ser 70Glu + Val103Pro + Asn106Asp + Ala168Pro
Thr113Gly + Gly162Ser + Asn163Asp + Asn170Glu
Leu104Ile + Ser107Glu + Gly110Asp + Asn170Gln
Thr 73Gly + Gly135Asp + Pro169Asp + Trp208Thr
Tyr210Met + Thr215Asp + Tyr218Glu + Leu221Asn
Leu104Thr + Gly136Glu + Pro169Asp + Leu221Val
Asn 66Asp + Thr 73Glu + Tyr218Ile + Leu221Cys
Asp105Glu + Thr111Asp + Ala114Pro + Val138Met
Asn 68Glu + Thr 73Glu + Trp208Tyr + Thr217Asn
Ser207Glu + Tyr213Ile + Ala219Asp + Ser222Asp
Asn163Asp + Ala164Ser + Ser191Asp + Ser207Glu
Thr 73Glu + Ala168Ser + Tyr210Glu + Tyr218Glu
Gly 67Glu + Trp208Ile + Pro214Asn + Thr215Asp
Asp105Glu + Thr111Glu + Thr113Glu + Asn163Gln
Ser 70Glu + Tyr210His + Thr217Asp + Leu221Ala
Gly 67Glu + Gly108Asp + Thr137Gln + Thr167Pro
Ser107Asp + Gly110Asp + Ala114Glu + Tyr218Asn
Ser 70Asp + Tyr210Glu + Thr217Asn + Ser220Glu
Thr113Gly + Trp208Glu + Ser220Asp + Thr224Asp
Val138Met + Ala219Glu + Ser222Asp + Thr224Gln
Ser 70Glu + Trp112Tyr + Tyr218Cys + Leu221Glu
Gly 67Ser + Ser 70Glu + Pro169Asn + Leu221Asp
Val115Cys + Gly139Asn + Thr217Asp + Ser220Asp
Gly 69Ser + Val115Thr + Thr217Glu + Ser220Glu
Ala168His + Trp208Tyr + Thr217Asp + Ser220Glu
Thr111Gln + Gly135Pro + Thr217Asp + Ser220Glu
Ala164Thr + Ser191Glu + Trp208Glu + Thr215Asn
Asn 68Glu + Val103Glu + Ser109Glu + Asn166Gln
Ser 70Asp + Gly139Ser + Thr217Glu + Ser220Asp
Leu134Asp + Phe193Glu + Ala203Ser + Gly223Asp
Asn 66Asp + Asn 68Ser + Ser216Asp + Thr217Glu
Ala164Glu + Trp208Cys + Leu221Glu + Ser222Asp
Ser 70Glu + Ser207Glu + Ala219Ser + Ser220Glu
Gly 67Asp + Ser 70Asp + Thr 73Gly + Tyr210Glu
Trp208Ile + Thr217Glu + Tyr218Asp + Ser222Asp
Leu104Ile + Thr111Glu + Gly135Asp + Asn163Gln
Ala114Glu + Leu134Ile + Ala219Glu + Ser220Asp
Asn166Glu + Thr167Gly + Ser222Asp + Gly223Asp
Gly139Glu + Tyr210Ala + Ser222Asp + Gly223Glu
Val103Gly + Gly110Glu + Thr111Glu + Ser222Glu
Ala114Glu + Asn170Ser + Ser216Asp + Thr217Glu
Gly108Asp + Ser109Asp + Tyr210Gln + Thr217Glu
Asn 68Ser + Ser109Asp + Gly110Glu + Ser220Glu
Asn 68Glu + Asn163Ser + Ser207Asp + Trp208Glu
Ser207Asp + Trp208Glu + Thr217Glu + Leu221Cys
Gly 69Pro + Asp105Glu + Asn106Asp + Asn166Asp
Ser109Asp + Tyr210Gln + Ser220Glu + Leu221Asp
Tyr171Gly + Ser192Glu + Ser220Asp + Leu221Glu
Asn170Glu + Ser191Glu + Ser192Glu + Pro205Ser
Asn 66Asp + Tyr210Gln + Thr217Glu + Tyr218Glu
Asn106Asp + Ser107Glu + Thr137Asp + Tyr210Gln
Ser192Asp + Phe193Glu + Pro205Ser + Thr217Asp
Ser 70Asp + Gly162Asp + Asn163Glu + Leu221Ser
Gly 69Asn + Asn106Glu + Tyr210Asp + Ser220Glu
Val103Ser + Asn140Asp + Tyr210Glu + Ser220Asp
Gly 69Glu + Phe193His + Ser207Glu + Ser222Asp
Gly162Glu + Asn163Gln + Trp208Asp + Ser220Glu
Val115Cys + Asn170Asp + Trp208Asp + Ser220Asp
Gly110Glu + Trp208Asp + Leu221Asn + Ser222Glu
Pro169Asp + Tyr171Glu + Pro214Asn + Gly223Glu
Asn163Glu + Ser207Glu + Trp208Met + Tyr210Thr
Gly 67Glu + Ser 70Glu + Val115Cys + Gly162Glu
Gly162Glu + Ala164Glu + Ser220Glu + Leu221Gly
Asn 66Glu + Val103Asp + Gly108Asn + Leu221Met
Asp105Glu + Ser109Glu + Tyr218Asp + Leu221Ala
Gly 67Asp + Ala164Asp + Ala168Glu + Tyr213Asn
Gly 69Pro + Ser141Asp + Pro214Asp + Thr217Asp
Thr 73Glu + Trp112Ile + Trp208Gly + Ser220Asp
Gly 72Ser + Ser107Asp + Thr111Asp + Asn166Gln
Gly165Glu + Ser192Asp + Thr217Asp + Leu221Ile
Gly135Glu + Asn140Glu + Ala204His + Pro214Ser
Asp105Glu + Gly110Asp + Asn170Asp + Ala219Gly
Asn 66Asp + Asn 68Asp + Leu134Gly + Asn163Glu
Leu104Thr + Ala168Asp + Asn170Asp + Ser220Glu
Thr 73Asp + Ser109Glu + Pro214Glu + Thr217Asn
Thr 73Asp + Val115Cys + Pro214Asp + Thr224Glu
Ser109Asp + Thr113Asp + Leu134Asn + Phe193Pro
Gly 69Ser + Gly108Asp + Gly110Asp + Ser220Glu
Gly139Asp + Ser141Asp + Ala164Asp + Leu221Val
Asn 66Asp + Trp208Met + Ser220Asp + Ser222Glu
Trp112Asp + Tyr210Thr + Ser220Glu + Ser222Glu
Ser109Asp + Ser207Glu + Tyr210Gly + Leu221Glu
Gly 69Asp + Asp105Glu + Thr137Asp + Trp208Asn
Ser109Asp + Thr111Glu + Ser191Glu + Tyr210Leu
Gly139Gln + Pro169Asp + Ser191Asp + Ser207Glu
Gly 67Ser + Asn140Asp + Ser222Asp + Thr224Glu
Val138Asp + Asn170Glu + Trp208His + Thr215Glu
Asn 68Asp + Thr111Gly + Val138Asp + Asn170Asp
Leu104Glu + Ser107Asp + Gly135Gln + Tyr171Asp
Leu104Pro + Trp112Asp + Asn140Glu + Ser222Glu
Gly139Glu + Asn170Asp + Gly206Pro + Ser220Glu
Ala164Asp + Asn170Asp + Ser216Asp + Thr217Pro
Thr113Glu + Ala114His + Ser207Glu + Ser220Glu
Gly110Glu + Val115Gln + Ser207Asp + Thr224Glu
Asn106Glu + Asn163Glu + Asn170Glu + Leu221His
Gly 69Asp + Thr 73Glu + Thr113Asn + Ser141Glu
Gly 69Asp + Thr 73Asp + Thr111Gly + Gly139Glu
Ser107Asp + Asn163Glu + Ser192Asp + Trp208Met
Asn 68Asp + Gly108Asp + Ser207Asp + Ile209Ala
Gly135Asp + Gly139Pro + Pro169Asp + Trp208Glu
Asn 66Glu + Thr167Gly + Trp208Glu + Pro214Asp
Asn 66Asp + Ser109Asp + Trp208Gly + Pro214Glu
Gly 69Glu + Asn140Ser + Ser192Glu + Pro214Asp
Leu104Gly + Gly139Glu + Ser191Asp + Thr224Asp
Asn106Gln + Thr113Asp + Asn163Asp + Asn166Glu
Leu134Glu + Ser207Asp + Trp208Pro + Tyr210Glu
Ser191Glu + Thr195Asn + Tyr218Pro + Leu221Glu
Asn170Asp + Phe193Ser + Ser220Glu + Thr224Asp
Asp105Glu + Ala114Glu + Ser192Glu + Thr224Asn
Gly 67Asp + Gly108Asp + Ser207Asp + Tyr210Cys
Asn 68Asp + Gly110Glu + Thr113Gly + Leu221Ala
Leu104Ile + Ala114Glu + Ser220Glu + Gly223Glu
Ser107Asp + Ser220Glu + Leu221Pro + Gly223Asp
Va1103Asp + Val138Glu + Ser141Glu + Gly206Gln
Val138Glu + Ser141Asp + Tyr210Gln + Ser220Asp
Asn 68Asp + Val115Gly + Thr217Asp + Ser220Glu
Asn 66Asp + Leu104Gly + Ala168Thr + Ser216Glu
Val103Glu + Asn106Glu + Thr113Pro + Ser220Asp
Asp105Glu + Thr113Asp + Gly139Asn + Ser141Glu
Ser 70Glu + Asp105Glu + Gly139Asp + Tyr210Ala
Asn 66Glu + Tyr210Asp + Thr217Glu + Leu221Ala
Gly108Glu + Gly135Ser + Tyr210Asp + Thr217Glu
Gly 69Asp + Gly108Gln + Trp112Asp + Ser141Glu
Ser107Glu + Gly110Pro + Thr217Asp + Ser220Asp
Gly135Glu + Thr217Glu + Tyr218Val + Ser220Glu
Asn163Asp + Tyr171Thr + Thr217Asp + Ser220Asp
Ala114Thr + Thr137Glu + Thr217Asp + Ser220Asp
Asn166Glu + Thr212Pro + Thr217Asp + Ser220Asp
Gly 67Asp + Ser107Asp + Tyr210Asn + Ser222Glu
Asn140Ser + Trp208Gly + Thr217Glu + Leu221Asp
Asn166Gln + Thr215Pro + Thr217Glu + Leu221Asp
Val115Gln + Ala168Gln + Phe193Asp + Leu221Asp
Trp208Ile + Pro214Ser + Ser220Glu + Thr224Glu
Gly108Glu + Thr137Glu + Asn163Asp + Trp208Ser
Gly139Pro + Ala164Glu + Ser191Asp + Pro214Glu
Thr 73Asp + Thr111Pro + Asn166Asp + Ser191Asp
Ser 70Glu + Ala168His + Thr195Glu + Ser216Asp
Ser109Glu + Thr137Asp + Gly139Ser + Ala164Gln
Asn170Gln + Tyr210Asp + Pro214Glu + Gly223Ser
Ser 70Glu + Gly139Asn + Ala164Glu + Ser220Asp
Asn 66Asp + Thr113Glu + Ser141Asp + Trp208Gly
Asn 66Asp + Gly108Glu + Thr215Gly + Leu221Ser
Asn 68Ser + Thr 73Glu + Asn166Glu + Leu221Asp
Thr 73Asp + Ser192Asp + Ser220Asp + Leu221Met
Ser107Asp + Thr111Asp + Ser192Glu + Thr217Ser
...
Table 35
Many ring five sudden change varient Asn 66Gln+Gly 67Ser+Leu104Gly+Tyr210Pro+
Thr217GluGly?69Ser?+?Val103Gln?+?Trp112Cys?+?Thr217Gly?+
Gly223AspVal115Pro?+?Leu134Ile?+?Ala164Glu?+?Phe193Asn?+
Trp208GlnLeu104Gly?+?Thr113Ser?+?Ala168Glu?+?Asn170Ser?+
Ala219GlyGly?69Ser?+?Ser109Asp?+?Thr111Gln?+?Val115Ala?+
Tyr210ProVal103Thr?+?Gly108Glu?+?Val115Pro?+?Tyr171Ser?+
Trp208AsnLeu134Ala?+?Val138Cys?+?Asn163Gln?+?Tyr171Ser?+
Ser220AspAsn?66Ser?+?Val115Gly?+?Ser191Glu?+?Trp208Ile?+
Thr217SerGly?72Asn?+?Trp112Phe?+?Val115Ala?+?Asn166Gln?+
Trp208GlyLeu134His?+?Gly165Gln?+?Trp208Pro?+?Tyr210Val?+
Thr217GluLeu104Pro?+?Tyr171Leu?+?Trp208Leu?+?Ala219Glu?+
Leu221SerAsn166Glu?+?Thr167Pro?+?Tyr210Pro?+?Tyr213Ile?+
Pro214AsnGly139Gln?+?Asn170Glu?+?Trp208Cys?+?Thr215Ser?+
Leu221AsnAla114Glu?+?Gly135Ser?+?Ala168Thr?+?Ala203Thr?+
Trp208MetAla164His?+?Ala168His?+?Phe193Ala?+?Thr217Ser?+
Ser220AspGly?67Pro?+?Gly?69Ser?+?Ser191Asp?+?Tyr218Val?+
Thr224SerGly139Asn?+?Ala164Pro?+?Phe193Pro?+?Thr217Asn?+
Leu221CysLeu104Met?+?Ser207Asp?+?Trp208Ala?+?Thr212Gly?+
Thr217ProLeu134Val?+?Trp208Thr?+?Pro214Gly?+?Leu221Ile?+
Thr224AspSerl09Asp?+?Ala114Asn?+?Val115Asn?+?Gly165Gln?+
Tyr210SerLeu104Ser?+?Gly110Pro?+?Gly136Glu?+?Ala168Thr?+
Ala219GlnGly110Pro?+?Leu134Pro?+?Asn166Asp?+?Asn170Ser?+
Trp208AsnThr113Gln?+?Pro169Gly?+?Asn170Gln?+?Tyr218Gln?+
Leu221SerThr137Ser?+?Thr195Gln?+?Ser207Glu?+?Trp208Gln?+
Thr217ProGly?69Gln?+?Val103Gly?+?Trp112Met?+?Trp208Asn?+
Pro214GlyGly136Pro?+?Gly162Ser?+?Trp208Ile?+?Tyr210Gly?+
Pro214GlnThr137Asp?+?Gly165Gln?+?Thr195Ser?+?Trp208Pro?+
Thr212SerAsn?66Ser?+?Pro169Ser?+?Tyr210Asn?+?Tyr218Asn?+
Gly223GluSer?70Glu?+?Asn106Gln?+?Val138Ala?+?Ala168Gln?+
Leu221ValGly?69Ser?+?Thr113Asp?+?Ala114Gln?+?Trp208Thr?+
Ala219SerThr113Gln?+?Ala168Asp?+?Pro169Ser?+?Asn170Ser?+
Ala219ThrGly139Ser?+?Asn170Gln?+?Tyr171Leu?+?Trp208Cys?+
Thr215SerGly?67Ser?+?Ala114Asn?+?Gly139Ser?+?Tyr210Thr?+
Tyr218SerTrp112Glu?+?Ala164Pro?+?Tyr171Pro?+?Thr195Asn?+
Thr217SerGly?67Glu?+?Val115Asn?+?Gly162Gln?+?Gly165Gln?+
Phe193ValGly135Ser?+?Tyr171Cys?+?Trp208His?+?Tyr210Met?+
Leu221ValGly?69Asn?+?Asn106Ser?+?Asn166Glu?+?Tyr210Cys?+
Leu221GlyGly135Ser?+?Tyr171Asn?+?Trp208His?+?Ser216Glu?+
Leu221GlyGly?69Asn?+?Ser109Asp?+?Gly165Asn?+?Phe193Asn?+
Trp208HisPro169Ser?+?Ser207Glu?+?Pro214Asn?+?Thr215Asn?+
Thr217GlySer?70Asp?+?Asn163Ser?+?Tyr210Val?+?Tyr213Asn?+
Leu221AlaGly108Gln?+?Gly110Ser?+?Gly135Gln?+?Thr137Asn?+
Trp208GluAsn?68Ser?+?Ala164Gln?+?Asn170Glu?+?Thr217Ser?+
Gly223SerGly?69Ser?+?Trp112Cys?+?Ala164Gly?+?Leu221Ser?+
Gly223GluGly?69Glu?+?Gly?72Gln?+?Thr137Pro?+?Trp208Ile?+
Tyr218ProVal103Gln?+?Val138His?+?Gly162Ser?+?Asn166Asp?+
Trp208HisVal115Gln?+?Leu134Cys?+?Ala168Ser?+?Pro169Asp?+
Tyr210SerGly?67Gln?+?Trp112Leu?+?Phe193His?+?Thr195Glu?+
Thr217SerGly?67Gln?+?Leu104Asn?+?Ala164Glu?+?Ala204Ser?+
Pro205SerGly135Ser?+?Val138Ser?+?Asn140Glu?+?Tyr210Leu?+
Thr217GlyGly?67Asn?+?Thr?73Ser?+?Tyr171Leu?+?Phe193Tyr?+
Tyr210ProGly135Pro?+?Trp208His?+?Tyr210Leu?+?Ala219Ser?+
Leu221GlnAsn?68Gln?+?Asn106Glu?+?Thr137Gln?+?Pro169Gln?+
Thr215GlnThr137Asp?+?Val138Gln?+?Trp208Ile?+?Tyr218Leu?+
Leu221CysGly?67Asn?+?Gly165Asn?+?Phe193Tyr?+?Pro205Ser?+
Trp208CysAsn?66Ser?+?Thr?73Ser?+?Ser107Asp?+?Ala168Ser?+
Tyr210CysThr137Gly?+?Tyr210Pro?+?Thr215Pro?+?Ser216Asp?+
Thr217SerThr?73Pro?+?Trp112Asp?+?Gly139Pro?+?Thr215Pro?+
Leu221HisLeu104Cys?+?Thr111Pro?+?Trp208Pro?+?Leu221Cys?+
Ser222AspThr113Gln?+?Ala204His?+?Trp208Phe?+?Thr217Asp?+
Leu221CysThr111Gly?+?Gly139Gln?+?Tyr171Leu?+?Tyr210Met?+
Thr217GluGly110Asn?+?Val115Gln?+?Pro169Gln?+?Thr195Gly?+
Ser220AspTyr171Asp?+?Gly206Ser?+?Thr217Gln?+?Ala219Gly?+
Leu221ThrSer109Glu?+?Thr111Ser?+?Val115Cys?+?Val138Cys?+
Tyr171SerLeu104His?+?Asn163Asp?+?Trp208Thr?+?Tyr210Cys?+
Thr217AsnGly136Asn?+?Gly139Pro?+?Ser141Glu?+?Pro169Gln?+
Ala219HisGly?69Ser?+?Gly136Ser?+?Thr137Asn?+?Thr195Pro?+
Ala219GluAsn106Asp?+?Gly162Ser?+?Asn163Gln?+?Pro169Gly?+
Leu221ProAla168Gly?+?Phe193Met?+?Pro205Asn?+?Tyr210Asn?+
Leu221AsnGly?69Pro?+?Gly139Asp?+?Ala164Gly?+?Tyr213Ser?+
Thr217SerGly?72Ser?+?Leu104Gln?+?Asn166Glu?+?Pro169Asn?+
Thr215GlyLeu134Cys?+?Trp208Asn?+?Tyr210Ala?+?Tyr218Gly?+
Thr224GlyLeu104Gln?+?Thr195Asn?+?Trp208Val?+?Tyr210Pro?+
Leu221CysGly?67Pro?+?Thr?73Asn?+?Trp208Pro?+?Ala219Asn?+
Ser220AspThr?73Gln?+?Gly108Pro?+?Gly139Pro?+?Ser192Glu?+
Gly223GlnAsn?68Glu?+?Thr?73Gln?+?Pro169Gln?+?Tyr210Pro?+
Leu221MetLeu104His?+?Thr113Gln?+?Asn140Gln?+?Thr167Asn?+
Phe193AspGly?67Pro?+?Asn?68Ser?+?Gly139Asp?+?Thr215Gly?+
Thr217ProGly136Ser?+?Val138Met?+?Thr167Gln?+?Tyr218Asn?+
Ser220AspAsp105Glu?+?Gly110Ser?+?Trp112His?+?Tyr210Gln?+
Ala219ThrAsn?68Asp?+?Asn106Gln?+?Ala164Ser?+?Thr195Gln?+
Trp208CysLeu104Val?+?Leu134Ala?+?Thr137Asn?+?Asn170Asp?+
Leu221IleGly?67Ser?+?Leu134Met?+?Trp208Ala?+?Tyr210Ser?+
Thr217ProAla114Gly?+?Gly135Asp?+?Gly139Ser?+?Asn170Ser?+
Thr217SerThr111Asn?+?Phe193Ser?+?Pro205Gln?+?Trp208Thr?+
Leu221GluSer109Asp?+?Val138Asn?+?Phe193Ala?+?Trp208Cys?+
Thr212GlnSer?70Asp?+?Asn166Ser?+?Ile209Pro?+?Tyr210Met?+
Leu221SerAsn106Ser?+?Leu134Cys?+?Gly136Ser?+?Ala168Thr?+
Tyr210GluGly?67Gln?+?Leu134Gln?+?Gly135Asp?+?Phe193His?+
Thr224GlyAsn?68Ser?+?Leu104Ala?+?Gly162Asp?+?Tyr171Met?+
Thr217GlyAsn163Glu?+?Thr212Gln?+?Thr215Asn?+?Thr217Asn?+
Leu221MetGly?69Gln?+?Asn106Gln?+?Ser207Glu?+?Trp208Thr?+
Thr217GlyGly139Glu?+?Ala168His?+?Thr195Gly?+?Leu221His?+
Thr224AsnGly?72Ser?+?Ala114Asn?+?Leu134His?+?Pro169Glu?+
Trp208TyrVal138Ser?+?Ala164Asn?+?Tyr210Cys?+?Tyr218Leu?+
Ser220AspLeu104Gln?+?Tyr171Glu?+?Trp208Gly?+?Thr217Gln?+
Ala219HisAsn106Ser?+?Tyr171Gly?+?Phe193Gln?+?Thr215Gln?+
Ala219GlnGly?72Ser?+?Gly108Asn?+?Trp112Ile?+?Asn166Glu?+
Leu221CysAsn?68Ser?+?Leu104Thr?+?Thr215Ser?+?Ala219Thr?+
Thr224AspVal138Ser?+?Asn163Asp?+?Phe193Cys?+?Pro205Asn?+
Thr217SerGly?67Ser?+?Tyr210Pro?+?Tyr218Thr?+?Ser220Asp?+
Leu221SerGly135Asn?+?Gly136Gln?+?Gly162Ser?+?Tyr210Asn?+
Pro214AsnThr195Ser?+?Trp208Pro?+?Tyr210Gly?+?Ala219Ser?+
Leu221IleAsn?68Glu?+?Thr111Pro?+?Asn163Ser?+?Phe193Tyr?+
Leu221ValGly?67Ser?+?Thr?73Pro?+?Asn170Glu?+?Tyr210Leu?+
Leu221ValGly135Asn?+?Gly139Ser?+?Phe193Asp?+?Thr217Gly?+
Leu221GlyGly136Gln?+?Gly139Gln?+?Gly165Ser?+?Tyr210Asp?+
Thr217ProSer141Glu?+?Gly162Pro?+?Thr167Gly?+?Tyr210Ile?+
Thr217SerLeu104Pro?+?Gly110Pro?+?Gly136Pro?+?Pro205Asn?+
Thr217GluVal115Ala?+?Ala164Thr?+?Ser192Asp?+?Trp208Leu?+
Tyr210MetThr?73Asn?+?Val103Asn?+?Thr215Asn?+?Thr217Gln?+
Ser222AspVal103Pro?+?Trp208Tyr?+?Ile209Cys?+?Tyr210Thr?+
Thr217GlnTrp112Phe?+?Ala114Ser?+?Pro169Gln?+?Ser220Glu?+
Leu221HisGly108Asn?+?Leu134Met?+?Tyr210Ser?+?Tyr213Ile?+
Pro214GluAla168Pro?+?Trp208His?+?Tyr210Ala?+?Ser220Glu?+
Leu221GlnGly139Pro?+?Asn140Glu?+?Ser141Asp?+?Asn166Ser?+
Trp208ThrVal103Asn?+?Thr111Gly?+?Tyr210Gln?+?Ser216Asp?+
Thr217GluVal138His?+?Gly139Asn?+?Ser207Asp?+?Trp208Glu?+
Leu221GlnAla168Asn?+?Pro169Gly?+?Thr217Pro?+?Ser220Asp?+
Leu221AspTyr210Leu?+?Ala219Gly?+?Ser220Asp?+?Leu221Asp?+
Gly223SerVal103Ala?+?Pro169Asn?+?Thr217Gln?+?Ser220Asp?+
Leu221AspThr?73Asn?+?Asn170Asp?+?Tyr171Glu?+?Tyr210Ile?+
Leu221SerGly136Ser?+?Ser191Asp?+?Ser192Glu?+?Tyr218Cys?+
Leu221AsnThr?73Pro?+?Val115Ala?+?Ser192Asp?+?Phe193Glu?+
Trp208GlnThr137Gln?+?Gly162Asp?+?Asn163Asp?+?Ala203His?+
Pro205GlnAsn163Gln?+?Tyr210Asp?+?Thr215Pro?+?Ser220Glu?+
Gly223ProAsp105Glu?+?Asn106Glu?+?Ser107Asp?+?Trp208Phe?+
Tyr210SerTrp112Gly?+?Phe193Gln?+?Ser207Asp?+?Trp208His?+
Ser222AspGly108Asn?+?Ser207Glu?+?Tyr213Thr?+?Thr215Pro?+
Ser222AspLeu134Met?+?Ser207Asp?+?Trp208Val?+?Tyr210His?+
Ser222AspGly?69Glu?+?Asn106Asp?+?Ala114His?+?Ala168Ser?+
Thr217GlnLeu104Pro?+?Trp208Glu?+?Thr212Asn?+?Thr215Ser?+
Ser222AspThr111Pro?+?Thr137Asn?+?Pro169Gln?+?Tyr210Glu?+
Ala219GluThr?73Gly?+?Val115Gly?+?Trp208Glu?+?Tyr210Asp?+
Ser220GluGly135Gln?+?Gly136Glu?+?Asn170Ser?+?Tyr171Glu?+
Trp208GlnThr?73Ser?+?Ser107Asp?+?Ser109Asp?+?Gly136Pro?+
Tyr210GlyLeu134Pro?+?Pro169Gln?+?Pro214Glu?+?Ser216Glu?+
Thr217GlyAsp105Glu?+?Ser109Glu?+?Pro169Gly?+?Tyr171Gln?+
Thr212SerGly135Pro?+?Val138Ala?+?Ser207Asp?+?Tyr210Thr?+
Gly223GluGly135Pro?+?Ser207Glu?+?Trp208Ala?+?Tyr210Pro?+
Gly223GluPro169Gln?+?Phe193Val?+?Tyr210Glu?+?Thr215Asn?+
Leu221AspAla114Gln?+?Gly136Ser?+?Ala219Asn?+?Ser220Asp?+
Ser222AspLeu134Ser?+?Thr167Gly?+?Ser220Asp?+?Leu221Pro?+
Ser222AspGly108Gln?+?Trp112Leu?+?Tyr218Glu?+?Ser220Asp?+
Leu221GluGly108Pro?+?Ala114Asn?+?Ser207Asp?+?Tyr210Glu?+
Ser220GluThr137Glu?+?Gly162Glu?+?Pro169Asn?+?Asn170Ser?+
Tyr171AspAsn?68Gln?+?Gly162Glu?+?Ala164Thr?+?Gly165Asp?+
Tyr171AlaThr137Pro?+?Gly139Asp?+?Asn170Glu?+?Trp208Met?+
Tyr210ThrAsn?68Gln?+?Val138Ser?+?Gly162Pro?+?Ala164Glu?+
Asn170AspAsn?68Gln?+?Ser207Glu?+?Trp208Thr?+?Thr217Ser?+
Ser220AspVal138Ala?+?Phe193Thr?+?Ser207Asp?+?Tyr210Met?+
Ser220AspPhe193Ala?+?Trp208Glu?+?Ile209Ser?+?Leu221Cys?+
Gly223GluThr111Gly?+?Phe193Gln?+?Ser207Asp?+?Ser220Asp?+
Gly223GluSer?70Asp?+?Asp105Glu?+?Gly108Glu?+?Thr111Ser?+
Tyr210ValGly136Glu?+?Gly162Asp?+?Gly165Ser?+?Ala168Pro?+
Thr195GluLeu104Gly?+?Gly165Glu?+?Pro169Glu?+?Thr217Asn?+
Leu221AlaThr195Asn?+?Tyr210Asp?+?Thr217Glu?+?Ser220Glu?+
Gly223ProTrp208Phe?+?Tyr210Asp?+?Tyr213Cys?+?Thr217Glu?+
Ser220GluSer?70Asp?+?Gly108Glu?+?Tyr171Gly?+?Thr217Gln?+
Leu221ProThr195Gly?+?Ser207Glu?+?Tyr210Glu?+?Tyr213Cys?+
Ala219SerAsn?68Glu?+?Asp105Glu?+?Gly110Asp?+?Thr111Pro?+
Asn140SerSer?70Asp?+?Val103Gln?+?Pro214Gln?+?Ser220Asp?+
Leu221GluAsn?66Asp?+?Thr?73Glu?+?Asn106Ser?+?Trp208His?+
Leu221ThrAla164Asp?+?Thr167Asp?+?Tyr171Pro?+?Ala219Gln?+
Leu221ThrAla114His?+?Ala219Gly?+?Ser220Glu?+?Ser222Glu?+
Thr224GluAsn106Asp?+?Ser109Asp?+?Thr111Asp?+?Thr137Ser?+
Pro205AsnLeu104Cys?+?Asn163Glu?+?Ser192Asp?+?Ala219Pro?+
Ser222GluGly162Asp?+?Ala164Gln?+?Ser207Asp?+?Trp208Tyr?+
Gly223AspSer?70Asp?+?Ser107Glu?+?Ser109Glu?+?Val115Cys?+
Gly135SerAla114Gly?+?Ala219Asp?+?Ser220Glu?+?Leu221Asn?+
Gly223GluAsn?66Asp?+?Asp105Glu?+?Val115Gln?+?Thr137Ser?+
Trp208HisGly?69Glu?+?Thr?73Glu?+?Val103His?+?Ser107Asp?+
Leu221AlaGly108Pro?+?Trp112Gln?+?Gly162Asn?+?Ser220Glu?+
Gly223AspAsn?68Asp?+?Asn170Gln?+?Tyr171Pro?+?Thr215Asp?+
Ser216AspSer?70Asp?+?Tyr171Ser?+?Thr195Gly?+?Tyr210Asp?+
Ser220GluThr113Gly?+?Gly162Ser?+?Trp208Glu?+?Ser220Asp?+
Thr224AspSer?70Glu?+?Asn140Ser?+?Ala203Gln?+?Ala219Glu?+
Gly223ProTrp112Pro?+?Asn170Ser?+?Ser216Asp?+?Thr217Asp?+
Ser220AspThr?73Asn?+?Val138Asp?+?Pro169Glu?+?Asn170Ser?+
Thr217GlySer?70Asp?+?Asp105Glu?+?Gly162Pro?+?Trp208Val?+
Thr217SerGly?67Asn?+?Asn140Ser?+?Ala219Glu?+?Leu221Met?+
Ser222GluGly?72Ser?+?Gly110Pro?+?Trp112Ala?+?Tyr210Asp?+
Thr217GluGly108Pro?+?Trp112Leu?+?Leu134Cys?+?Gly135Asp?+
Ala164AspAsn?66Gln?+?Trp208Ala?+?Thr217Glu?+?Ser220Glu?+
Leu221ThrThr?73Gly?+?Leu134Ser?+?Thr217Glu?+?Ser220Glu?+
Leu221AsnGly?67Ser?+?Ala168Gly?+?Pro214Gln?+?Thr217Glu?+
Ser220AspVal115Cys?+?Glyl39Asn?+?Tyr210Cys?+?Thr217Asp?+
Ser220AspLeu134Glu?+?Thr137Glu?+?Thr195Asn?+?Trp208Ser?+
Leu221SerAla164Gln?+?Tyr210Val?+?Thr215Asp?+?Thr217Glu?+
Ser220AspGly?67Asp?+?Ser?70Asp?+?Thr217Gly?+?Tyr218Asp?+
Leu221IleSer?70Asp?+?Thr111Asn?+?Trp208Cys?+?Thr217Glu?+
Ser220GluLeu134Glu?+?Gly162Ser?+?Asn166Gln?+?Ser207Asp?+
Gly223AspGly162Pro?+?Thr167Asn?+?Pro169Glu?+?Ser191Glu?+
Phe193AspSer?70Glu?+?Trp112Tyr?+?Ser207Glu?+?Tyr218Cys?+
Leu221GluAsn?66Glu?+?Leu104Glu?+?Ser107Asp?+?Trp208Ser?+
Thr215ProLeu104Ala?+?Gly135Asp?+?Thr195Asp?+?Tyr213Ile?+
Thr217GlyThr167Gln?+?Ser192Glu?+?Ser207Glu?+?Trp208Cys?+
Ser220AspGly165Pro?+?Ser191Asp?+?Trp208Gly?+?Ser220Asp?+
Leu221GluGly135Glu?+?Asn163Asp?+?Tyr213Met?+?Leu221His?+
Ser222AspThr111Asp?+?Gly136Glu?+?Gly162Glu?+?Ala164Asn?+
Pro214SerThr113Gln?+?Tyr213Thr?+?Ser216Glu?+?Thr217Glu?+
Leu221GluSer?70Glu?+?Glyl08Glu?+?Ala164Gly?+?Gly165Gln?+
Leu221AspSer?70Glu?+?Leu104Gln?+?Ser220Asp?+?Leu221His?+
Gly223ProGly165Asp?+?Pro169Ser?+?Ser207Glu?+?Trp208Gly?+
Ser222AspAla168Pro?+?Pro169Asn?+?Thr215Asp?+?Thr217Asp?+
Leu221GluGly110Pro?+?Thr113Ser?+?Gly165Glu?+?Trp208Asp?+
Ser222AspGly110Glu?+?Thr113Asp?+?Gly139Glu?+?Trp208Tyr?+
Tyr210AlaAsn?68Glu?+?Asn106Glu?+?Tyr171His?+?Tyr210Gln?+
Ser216GluAla164Glu?+?Ala168His?+?Ala219Glu?+?Ser220Asp?+
Leu221CysAsn?68Asp?+?Tyr210Gln?+?Ala219Glu?+?Ser220Glu?+
Leu221SerThr?73Asp?+?Asn163Ser?+?Ala219His?+?Ser222Glu?+
Gly223GluGly?67Asp?+Asn?68Glu?+?Ala168Gln?+?Pro169Glu?+
Phe193AsnGly110Asp?+?Gly139Gln?+?Asn140Glu?+?Ser141Glu?+
Tyr218AsnSer109Glu?+?Ser216Glu?+?Thr217Asp?+?Tyr218Asn?+
Leu221HisGly135Pro?+?Gly136Ser?+?Phe193Asp?+?Ser216Asp?+
Thr217GluGly165Gln?+?Ser192Glu?+?Ala203Ser?+?Ser216Asp?+
Thr217AspGly?67Gln?+?Leu134His?+?Gly136Asp?+?Ser207Asp?+
Trp208GluVal103Ser?+?Ser207Asp?+?Trp208Glu?+?Thr217Glu?+
Leu221CysGly?69Pro?+?Asp105Glu?+?Asn106Asp?+?Asn166Asp?+
Ile209ThrTrp112Tyr?+?Asn170Glu?+?Trp208Gln?+?Ser220Glu?+
Leu221GluThr137Gly?+?Gly139Gln?+?Gly162Asp?+?Ser220Glu?+
Leu221AspThr113Asp?+?Ala164Gly?+?Ser191Glu?+?Ser192Glu?+
Thr195GlySer107Glu?+?Thr113Glu?+?Ala114Asp?+?Tyr210Pro?+
Leu221AlaAsn?66Asp?+?Gly?67Asp?+?Leu134Pro?+?Tyr210Asn?+
Ser222AspAsn?68Gln?+?Leu104Ala?+?Pro169Asp?+?Asn170Glu?+
Leu221AspAsn106Glu?+?Ser107Asp?+?Gly139Asp?+?Ala203Asn?+
Thr217SerThr?73Gly?+?Thr137Glu?+?Tyr210Asp?+?Thr217Gln?+
Ser220GluTrp112Ile?+?Gly136Glu?+?Phe193Thr?+?Tyr210Glu?+
Ser220GluTrp112Ala?+?Asn163Ser?+?Ser192Glu?+?Tyr210Glu?+
Ser220GluSer?70Glu?+?Thr?73Ser?+?Val103Asp?+?Pro214Glu?+
Tyr218GlyAsn106Glu?+?Ser109Glu?+?Thr195Gln?+?Trp208Pro?+
Pro214GluAsn?68Gln?+?Val103Asp?+?Thr137Gln?+?Ser207Asp?+
Ser222AspThr137Asp?+?Ser207Glu?+?Thr217Gly?+?Leu221Pro?+
Ser222AspGly?69Asp?+?Thr?73Glu?+?Thr111Pro?+?Gly139Asn?+
Ser220AspAsn?66Glu?+?Ser?70Asp?+?Pro214Gly?+?Ser220Glu?+
Leu221SerSer?70Glu?+?Leu104Cys?+?Tyr210Ser?+?Thr215Glu?+
Ser220GluThr167Pro?+?Ser216Glu?+?Ala219Glu?+?Leu221Met?+
Ser222AspVal138Asp?+?Asn166Glu?+?Thr167Asp?+?Ala168Thr?+
Leu221AlaLeu134Pro?+?Serl41Glu?+?Trp208Glu?+?Thr217Ser?+
Ser220GluGly135Glu?+?Tyr171Asn?+?Pro205Gln?+?Trp208Glu?+
Ser220AspTrp112Asn?+?Thr167Glu?+?Ala168Gly?+?Trp208Asp?+
Ser220GluAsn140Asp?+?Pro169Gln?+?Trp208Glu?+?Thr215Gln?+
Ser220GluAsn106Gln?+?Gly136Asp?+?Trp208Glu?+?Thr217Ser?+
Ser220GluAsn106Asp?+?Thr111Asn?+?Thr167Gly?+?Tyr210Asp?+
Ala219AspAsn?66Gln?+?Pro169Asp?+?Tyr171Glu?+?Pro214Asn?+
Gly223GluTrp112Gly?+?Asn163Asp?+?Thr167Glu?+?Ser191Glu?+
Gly223SerTrp112Asp?+?Thr113Ser?+?Ala114Glu?+?Thr217Glu?+
Gly223GlnAsn?66Asp?+?Thr?73Gly?+?Val103Asp?+?Thr111Pro?+
Thr195AsnAsn?68Asp?+?Trp112Met?+?Trp208Asn?+?Pro214Asp?+
Ser220AspAsp105Glu?+?Ser109Glu?+?Asn163Glu?+?Asn166Ser?+
Tyr218GlyGly110Gln?+?Trp112Asp?+?Leu134Pro?+?Pro214Asp?+
Thr217AspGly?67Pro?+?Thr113Glu?+?Gly135Asp?+?Gly162Asp?+
Thr215GlnSer?70Glu?+?Thr195Ser?+?Pro214Ser?+?Ser220Glu?+
Gly223GluGly110Pro?+?Val138Glu?+?Trp208Glu?+?Tyr210Glu?+
Thr217GlyGly108Asn?+?Asn163Glu?+?Ala219Asp?+?Leu221Val?+
Thr224AspThr?73Asp?+?Gly108Asn?+?Ser109Glu?+?Pro214Glu?+
Thr217AsnThr137Asp?+?Gly139Glu?+?Asn170Ser?+?Trp208Cys?+
Tyr210AspTrp112Phe?+?Gly139Glu?+?Tyr213Thr?+?Ala219Glu?+
Leu221GluLeul04Pro?+?Pro169Glu?+?Tyr210Glu?+?Leu221Asp?+
Thr224GlyAsp105Glu?+?Gly165Glu?+?Thr167Gln?+?Ala168Glu?+
Tyr210ProThr137Asp?+?Trp208Asn?+?Tyr218Ser?+?Ser220Asp?+
Ser222AspGly?69Glu?+?Thrll3Gln?+?Thr217Ser?+?Ser220Glu?+
Ser222GluLeu104His?+?Thr113Asp?+?Ser207Asp?+?Thr217Ser?+
Leu221GluAla114Thr?+?Gly135Asp?+?Ser207Asp?+?Thr217Ser?+
Leu221AspGly?69Ser?+?Leu104Asp?+?Asn106Glu?+?Ser191Glu?+
Thr217GlyVal103Ala?+?Tyr171Val?+?Ser207Asp?+?Ser216Asp?+
Tyr218AspGly?69Ser?+?Leu134Ile?+?Gly162Asp?+?Ser207Glu?+
Ser220GluGly?72Pro?+?Thr113Glu?+?Asn166Asp?+?Thr167Asp?+
Thr217GlnAsn166Glu?+?Thr167Asp?+?Ser207Glu?+?Thr217Gly?+
Leu221ValThr111Asn?+?Trp112Glu?+?Val138Gly?+?Asn163Asp?+
Tyr171GluGly?67Pro?+?Asn106Glu?+?Leu134Pro?+?Thr137Asp?+
Pro169GluThr195Glu?+?Ser207Asp?+?Ser220Asp?+?Leu221Val?+
Thr224GlyAsn?68Asp?+?Gly?69Gln?+?Gly162Asp?+?Pro169Ser?+
Gly223AspThr?73Ser?+?Gly165Asn?+?Ser207Asp?+?Tyr210Asp?+
Ser216GluVal103Glu?+?Ala164Asp?+?Asn170Glu?+?Trp208Ala?+
Tyr210IleAla114Thr?+?Ala164Asp?+?Asn170Glu?+?Tyr210Ala?+
Thr215AspAsn?68Glu?+?Gly139Pro?+?Ala164Pro?+?Ser191Asp?+
Pro214GluAsn?68Glu?+?Ala164Glu?+?Gly165Ser?+?Tyr210Gly?+
Pro214AspGly?67Ser?+?Thr167Gly?+?Ser207Glu?+?Ser216Asp?+
Ser220AspAsp105Glu?+?Gly110Asn?+?Ser207Asp?+?Ala219Gly?+
Ser220GluVal103Gly?+?Asn140Asp?+?Ser207Asp?+?Tyr213Asn?+
Ser220AspSer109Glu?+?Gly165Asn?+?Ser207Glu?+?Tyr210Cys?+
Ser220AspGly110Asn?+?Asn140Glu?+?Ser207Glu?+?Thr217Ser?+
Ser220GluGly110Asp?+?Gly136Pro?+?Gly206Gln?+?Ser207Glu?+
Ser220GluThr113Gln?+?Leu134Ile?+?Ser192Glu?+?Thr195Asp?+
Ser220AspGly136Glu?+?Trp208Glu?+?Thr217Gly?+?Leu221Asn?+
Gly223AspSer107Asp?+?Gly110Asp?+?Leu134Ser?+?Asn140Glu?+
Tyr210ThrThr167Glu?+?Trp208Asp?+?Thr217Asn?+?Ala219Asp?+
Gly223AsnGly?69Glu?+?Ala114Asp?+?Thr195Ser?+?Trp208Ser?+
Pro214GluVal103Asp?+?Thr113Glu?+?Phe193Tyr?+?Trp208Asp?+
Ala219ProAsn106Asp?+?Gly136Ser?+?Val138Met?+?Ser191Asp?+
Ser222AspGly135Asp?+?Gly139Glu?+?Tyr210Ala?+?Thr217Ser?+
Ser222AspThr113Asp?+?Asn140Ser?+?Ala203Gln?+?Ser207Glu?+
Tyr210GluGly108Glu?+?Thr113Gln?+?Ser207Glu?+?Tyr210Asp?+
Pro214AsnGly135Glu?+?Asn163Asp?+?Tyr210Met?+?Tyr218Pro?+
Ser220AspAsn163Asp?+?Ala164Thr?+?Ser191Glu?+?Thr217Asp?+
Thr224GlnAsn?68Glu?+?Leu104Asp?+?Val115Thr?+?Ala164Asp?+
Pro214GlnThr?73Gly?+?Ser107Glu?+?Gly108Pro?+?Leu221Glu?+
Thr224AspGly?67Ser?+?Gly162Asp?+?Thr167Asp?+?Ser207Glu?+
Thr217SerGly?67Gln?+?Ser109Glu?+?Val138Ser?+?Pro214Glu?+
Ala219GluSer107Glu?+?Gly135Glu?+?Trp208His?+?Thr217Ser?+
Thr224GluAsn?66Glu?+?Asp105Glu?+?Val138His?+?Ser192Glu?+
Tyr210IleAsn?66Glu?+?Asp105Glu?+?Ala219Gln?+?Ser220Glu?+
Leu221AsnGly?69Ser?+?Ser?70Glu?+?Gly110Glu?+?Thr217Asp?+
Leu221AlaTyr171Glu?+?Ser192Asp?+?Ser207Glu?+?Trp208Pro?+
Tyr210MetGly?67Gln?+?Asp105Glu?+?Ala164Asp?+?Pro169Asn?+
Gly223AspThr?73Asp?+?Ser141Asp?+?Trp208Leu?+?Ser216Glu?+
Thr217ProAsn?66Asp?+?Trp208Gln?+?Ile209Thr?+?Tyr210Val?+
Ser216GluAsn?66Ser?+?Val103Glu?+?Asn106Asp?+?Ser191Glu?+
Tyr210AlaAsn?68Gln?+?Leu134Glu?+?Ser192Glu?+?Leu221Gly?+
Ser222GluSer?70Asp?+?Asp105Glu?+?Gly108Ser?+?Gly139Glu?+
Thr217GlyGly?67Ser?+?Asn106Asp?+?Gly165Gln?+?Ala219Asp?+
Ser222GluAsn106Gln?+?Leu134Met?+?Asn140Asp?+?Ala219Asp?+
Ser222AspGly?69Glu?+?Val103Gln?+?Leu134Asp?+?Thr167Gln?+
Trp208GlyThr137Glu?+?Gly165Glu?+?Tyr210Ser?+?Thr217Ser?+
Leu221ProSer107Asp?+?Gly162Asp?+?Thr167Asp?+?Tyr171Cys?+
Trp208IleAsn106Glu?+?Trp112Asp?+?Leu134Gly?+?Ser141Glu?+
Phe193SerAla114Thr?+?Asn140Asp?+?Phe193Thr?+?Thr217Glu?+
Ser220GluThr113Ser?+?Val115Asp?+?Leu134Val?+?Thr217Asp?+
Ser220GluGly110Asp?+?Asn170Gln?+?Thr217Glu?+?Tyr218Ala?+
Ser220AspThr167Asp?+?Phe193Thr?+?Thr217Asp?+?Ala219Gln?+
Ser220AspGly108Glu?+?Pro214Asn?+?Thr217Glu?+?Ser220Asp?+
Leu221ValAsn106Gln?+?Gly135Glu?+?Val138His?+?Thr217Glu?+
Ser220GluGly110Glu?+?Tyr210Met?+?Thr217Glu?+?Ser220Asp?+
Leu221HisGly?67Glu?+?Ser107Glu?+?Gly110Ser?+?Thr113Glu?+
Thr215SerGly?67Glu?+?Ser107Glu?+?Thr111Pro?+?Ala168His?+
Ser220GluThr111Asp?+?Gly136Asp?+?Trp208Glu?+?Tyr210Met?+
Thr217GlnAsp105Glu?+?Gly162Ser?+?Asn166Asp?+?Ser191Asp?+
Trp208PheAsp105Glu?+?Asn166Glu?+?Ser191Glu?+?Trp208Ala?+
Leu221HisGly?67Glu?+?Val103Glu?+?Ala164Asn?+?Ser207Asp?+
Tyr218AlaGly?72Asn?+?Leu104Asp?+?Asn106Gln?+?Thr113Asp?+
Thr217AspSer?70Asp?+?Gly135Glu?+?Ala168Glu?+?Tyr210Ile?+
Ala219GlyAsn106Gln?+?Ser109Glu?+?Thr113Asp?+?Thr137Glu?+
Trp208AsnAla114Ser?+?Val138Thr?+?Pro169Asn?+?Phe193Asp?+
Trp208GluAsn?68Asp?+?Val138Asp?+?Ala164Gly?+?Ala168Glu?+
Thr217GlyGly?69Asn?+?Val138Asp?+?Ala168Glu?+?Ser207Asp?+
Thr217ProGly110Ser?+?Thr111Gln?+?Ala164Glu?+?Thr215Ser?+
Ser222AspLeu104Ser?+?Gly108Glu?+?Val115Glu?+?Val138His?+
Ser141GluSer?70Glu?+?Ala114Ser?+?Thr137Ser?+?Ser207Asp?+
Ser216AspGly?69Asp?+?Gly110Asp?+?Thr137Glu?+?Pro169Ser?+
Tyr171HisSer?70Asp?+?Thr137Glu?+?Ala164His?+?Trp208Ile?+
Ser220GluSer?70Glu?+?Thr137Glu?+?Thr217Asn?+?Ser220Glu?+
Gly223AsnGly110Gln?+?Trp112Cys?+?Val115Glu?+?Asn140Asp?+
Ser216GluAsn?68Asp?+?Ser109Glu?+?Asn166Gln?+?Trp208Pro?+
Leu221AspThr113Pro?+?Thr167Glu?+?Tyr171Glu?+?Thr217Gln?+
Ser220GluTrp112Ile?+?Leu134His?+?Gly139Asp?+?Gly162Glu?+
Trp208ValGly110Asp?+?Gly162Gln?+?Trp208Ile?+?Tyr210Glu?+
Gly223AspGly?67Asp?+?Thr111Asp?+?Trp208Val?+?Tyr210Ser?+
Ser216GluGly?69Asn?+?Thr?73Glu?+?Asn106Asp?+?Ser141Glu?+
Gly162AsnGly?69Glu?+?Gly135Asn?+?Pro169Asn?+?Trp208Ala?+
Thr217GluAla203Gly?+?Trp208Ala?+?Pro214Glu?+?Ala219Gln?+
Leu221AspThr?73Gly?+?Gly110Glu?+?Pro214Asp?+?Ser220Glu?+
Leu221AsnVal103Ala?+?Thr167Gly?+?Ser192Glu?+?Pro214Glu?+
Ser220AspAsp105Glu?+?Tyr171Gln?+?Pro214Asp?+?Thr217Ser?+
Ser220AspTyr171Val?+?Ser191Asp?+?Trp208Pro?+?Pro214Glu?+
Ser220GluGly?67Asp?+?Gly162Ser?+?Gly206Ser?+?Ser207Glu?+
Thr217GluGly?67Glu?+?Trp112Phe?+?Ser207Asp?+?Thr217Asp?+
Ala219GlnAsn?68Asp?+?Asn163Glu?+?Phe193Met?+?Gly206Ser?+
Leu221GluAsn?66Asp?+?Leu104Ala?+?Ser109Glu?+?Ala168Thr?+
Ser216GluVal138Met?+?Gly139Asp?+?Gly162Ser?+?Ala168Glu?+
Ser220Asp
Table 36
Polycyclic six mutant
Asn 66Gln + Gly 67Ser + Gly 69Ser + Leu104Gly +
Tyr210Pro + Thr217Glu
Ser 70Asp + Gly110Pro + Gly136Gln + Phe193Ser +
Trp208Cys + Leu221His
Thr113Pro + Gly139Asn + Ser141Glu + Tyr171Pro +
Trp208Thr + Leu221Gly
Gly 69Gln + Leu104Thr + Ser107Asp + Leu134Thr +
Thr215Ser + Leu221Gly
Leu104Met + Leu134Ala + Thr137Asp + Trp208Gly +
Tyr210Val + Pro214Gly
Gly 69Ser + Thr 73Asp + Gly110Ser + Tyr210Leu +
Thr215Gly + Thr217Ser
Asn 66Ser + Gly 72Gln + Thr 73Pro + Gly110Asp +
Trp208Val + Leu221His
Thr111Asn + Ala164His + Thr167Glu + Phe193Met +
Tyr210Asn + Thr217Gln
Asn 66Gln + Thr 73Gly + Thr113Asp + Asn166Ser +
Thr167Pro + Tyr210Pro
Leu104Met + Pro205Gln + Ser207Asp + Trp208Ala +
Thr212Gly + Thr217Pro
Leu134Val + Gly165Gln + Trp208Thr + Pro214Gly +
Leu221Ile + Thr224Asp
Asn 66Ser + Ser109Asp + Ala114Asn + Val115Asn +
Trp208Gln + Tyr210Ser
Asn106Gln + Ala164Pro + Gly165Ser + Tyr171Ala +
Ser220Glu + Thr224Ser
Gly110Ser + Gly136Pro + Ile209His + Thr217Gln +
Leu221Ile + Thr224Asp
Asn 66Gln + Val115Pro + Trp208Asp + Thr217Ser +
Leu221Ile + Thr224Pro
Gly 67Glu + Thr 73Asn + Asn170Ser + Tyr210Ser +
Thr212Gln + Gly223Pro
Val103Gly + Ala164Thr + Tyr210His + Ala219His +
Ser220Glu + Leu221Gly
Thr 73Pro + Asn140Gln + Thr167Asp + Trp208Met +
Thr217Gln + Leu221Asn
Ser109Asp + Ala164His + Tyr210Pro + Thr212Ser +
Gly223Pro + Thr224Asn
Gly110Gln + Tyr210Pro + Tyr213Thr + Tyr218Met +
Ser220Asp + Leu221His
Val138Pro + Ala168Gly + Pro169Gln + Tyr210Ser +
Thr217Gln + Ser220Asp
Ala114Thr + Thr137Asn + Gly139Ser + Trp208Pro +
Pro214Gln + Ser220Glu
Val103Met + Thr137Ser + Ala203Ser + Tyr210Thr +
Leu221Met + Gly223Ser
Leu104Glu + Thr111Ser + Val115His + Gly165Asn +
Tyr210Met + Ala219His
Gly110Pro + Leu134Pro + Asn166Asp + Asn170Ser +
Trp208Asn + Thr217Asn
Thr167Glu + Pro169Gly + Asn170Gln + Trp208Gly +
Thr215Ser + Leu221Ser
Thr111Ser + Thr137Ser + Thr195Gln + Ser207Glu +
Tyr210Val + Thr217Pro
Asn106Asp + Gly136Pro + Gly162Ser + Trp208Ile +
Tyr210Gly + Pro214Gln
Ser 70Asp + Gly165Gln + Phe193Asn + Thr195Ser +
Trp208Pro + Thr212Ser
Gly 72Ser + Ala114Gln + Asn166Gln + Phe193Glu +
Tyr210Gly + Thr224Pro
Asn 66Ser + Gly136Ser + Gly162Pro + Asn163Ser +
Ala164Asp + Ala168Gln
Gly 67Pro + Asn106Gln + Ser191Asp + Trp208His +
Tyr218His + Leu221Asn
Trp112Leu + Ala168Pro + Trp208His + Tyr210Ser +
Thr217Gly + Ser220Asp
Asn 66Ser + Thr111Gly + Val115Gly + Ala168Ser +
Asn170Gln + Pro214Gly
Gly110Ser + Trp112Val + Gly162Asn + Thr167Pro +
Pro169Gln + Ser216Asp
Gly 69Asn + Asn106Ser + Gly139Glu + Asn170Ser +
Tyr210Cys + Leu221Gly
Gly 69Asn + Ser141Asp + Phe193Asn + Tyr210Ile +
Ala219Asn + Leu221Ser
Ser109Asp + Pro169Ser + Trp208His + Pro214Asn +
Thr215Asn + Thr217Gly
Asn 68Asp + Gly162Gln + Ala164His + Trp208Pro +
Tyr210Leu + Leu221Val
Val103Thr + Gly139Pro + Ala164Thr + Thr217Ser +
Leu221Pro + Thr224Pro
Gly 69Glu + Gly 72Gln + Thr137Pro + Trp208Ile +
Tyr218Pro + Gly223Gln
Gly 67Pro + Leu104Cys + Val138Met + Gly139Ser +
Ala203Gln + Ala219Asn
Trp112Ser + Phe193Ala + Thr217Gly + Tyr218Glu +
Leu221Met + Thr224Asn
Asn163Gln + Trp208Leu + Tyr210Ser + Thr217Glu +
Ala219Gly + Gly223Pro
Val103His + Gly110Gln + Gly139Ser + Ser192Asp +
Phe193Asn + Thr217Gln
Gly108Gln + Pro169Asn + Thr195Ser + Trp208Ala +
Thr215Pro + Thr217Glu
Ser109Asp + Thr111Asn + Trp112Gln + Thr167Gln +
Thr195Gly + Tyr210Asn
Gly 72Gln + Trp112Leu + Gly136Asp + Tyr171His +
Tyr210Thr + Leu221Ser
Gly 69Glu + Ala164Pro + Trp208Val + Tyr210Thr +
Tyr218Gln + Thr224Ser
Ala114Pro + Leu134Glu + Asn140Ser + Ala164Gln +
Phe193Ile + Trp208Asn
Asn 66Ser + Val138Met + Gly139Asn + Asn163Gln +
Gly165Gln + Tyr210Thr
Asn106Gln + Ser191Asp + Phe193Leu + Trp208Val +
Pro214Gln + Thr217Ser
Ala114Thr + Asn166Ser + Tyr171Gly + Ser191Glu +
Ala203Pro + Tyr210Ala
Asn 68Gln + Tyr171Asp + Phe193Tyr + Gly206Ser +
Tyr210Val + Leu221Thr
Leu104Ala + Alal14Ser + Asn163Asp + Thr195Gly +
Gly206Gln + Leu221Ala
Gly110Asn + Val115Asn + Trp208Cys + Tyr210His +
Ala219Thr + Gly223Asp
Asn 66Asp + Gly 69Asn + Val115Ala + Ala164Ser +
Trp208Gln + Thr217Gln
Val115Met + Thr137Ser + Gly162Asn + Asn166Glu +
Tyr171His + Pro214Ser
Asn106Gln + Gly110Gln + Trp208His + Thr217Pro +
Ala219Asp + Ser220Asp
Gly 67Asn + Gly 72Asn + Ala114Gly + Asn140Gln +
Ser216Asp + Thr217Asp
Gly 69Gln + Thr 73Ser + Pro169Gln + Trp208Ile +
Ser220Glu + Leu221Asp
Asn170Glu + Tyr171Asp + Phe193Ser + Trp208His +
Leu221Thr + Thr224Gly
Gly 67Ser + Gly 69Glu + Ser 70Glu + Val103Gly +
Tyr210Gln + Ala219Asn
Trp112Gly + Asn166Ser + Trp208Met + Tyr210Glu +
Ser220Glu + Thr224Asn
Leu134Pro + Thr195Gly + Trp208Glu + Tyr210Asp +
Thr217Ser + Ser220Glu
Leu104Gln + Trp112Gln + Tyr171Pro + Trp208Glu +
Thr217Gly + Leu221Glu
Asp105Glu + Gly108Asp + Gly136Gln + Thr167Gln +
Tyr171Gln + Leu221Val
Ser107Glu + Ser109Glu + Val138Met + Ala168His +
Pro169Gln + Phe193Ser
Gly 67Glu + Ser 70Glu + Trp112His + Tyr171Ile +
Trp208His + Tyr210Ala
Val103Pro + Trp208Glu + Tyr210Ser + Ala219Glu +
Ser220Glu + Ser222Asp
Ser191Asp + Ser207Glu + Tyr210Ala + Thr215Gly +
Thr217Gln + Gly223Ser
Asn106Glu + Ser109Asp + Ala168Thr + Tyr171Met +
Phe193Ile + Trp208Leu
Asn 68Ser + Thr137Gln + Ser191Asp + Ser207Asp +
Trp208Asp + Leu221Thr
Val103Gln + Val138His + Asn166Asp + Ser192Glu +
Trp208His + Leu221Gly
Val103Pro + Gly139Pro + Asn163Asp + Gly165Gln +
Ala168Glu + Tyr210Leu
Asn 68Ser + Thrl13Gln + Leu134Ile + Ser191Glu +
Leu221His + Gly223Glu
Gly110Gln + Ser207Glu + Trp208Gln + Thr217Pro +
Tyr218Gly + Ser220Asp
Gly162Ser + Phe193Ala + Trp208Glu + Ile209Ser +
Leu221Cys + Gly223Glu
Ser 70Asp + Asp105Glu + Gly108Glu + Asn140Gln +
Trp208Leu + Thr217Gly
Glyl10Asn + Thr137Glu + Pro169Asp + Asn170Ser +
Thr195Glu + Tyr210His
Asn 68Gln + Gly162Glu + Ala164Thr + Gly165Asp +
Tyr171Ala + Ser192Asp
Val138Met + Gly139Asn + Asn170Gln + Tyr210Glu +
Thr217Asp + Ser220Glu
Gly139Ser + Asn163Asp + Ala164Ser + Ser191Asp +
Tyr210Gly + Leu221Ala
Ser 70Asp + Thr 73Asp + Thr167Ser + Trp208Ser +
Thr217Asp + Ala219Asp
Asn 66Glu + Leu104Glu + Asp105Glu + Ser107Asp +
Leu221Ser + Gly223Pro
Asn 66Glu + Thr 73Asp + Gly110Pro + Ala168Gly +
Tyr218Val + Leu221Ile
Gly 67Asn + Asp105Glu + Asn106Glu + Thr111Glu +
Gly165Asn + Thr217Gly
Asn 66Asp + Tyr210Ser + Pro214Glu + Thr215Asp +
Thr217Gln + Tyr218Asp
Thr 73Asn + Ser192Glu + Ala203Thr + Ser207Asp +
Trp208Glu + Leu221Glu
Val138Gly + Pro169Glu + Ser192Glu + Thr195Glu +
Trp208Pro + Thr212Gln
Thr 73Asp + Gly108Asn + Leu134Ser + Tyr210Ala +
Thr217Gln + Tyr218Glu
Thr 73Asn + Ala114Thr + Val138Ser + Gly139Asp +
Ser141Glu + Asn170Glu
Gly108Gln + Gly135Pro + Gly162Asn + Ser220Glu +
Leu221Ala + Gly223Glu
Val103Gln + Trp112Cys + Ala164Glu + Trp208Gln +
Thr217Gly + Gly223Asp
Thr111Gln + Leu134His + Ser191Asp + Phe193Asp +
Thr195Gln + Trp208Asp
Val103Ser + Leu104Ile + Gly110Glu + Gly136Glu +
Ala164Asn + Tyr210Gln
Leu134Ser + Thr167Gly + Ser191Glu + Ser220Asp +
Leu221Pro + Ser222Asp
Gly 69Gln + Trp208Asp + Pro214Glu + Ser220Asp +
Ser222Glu + Gly223Asn
Ser107Asp + Ser109Glu + Trp112Pro + Gly135Asp +
Ala168Thr + Thr212Gly
Asn140Ser + Thr167Asp + Trp208Glu + Thr217Asn +
Ser220Asp + Leu221Asp
Gly135Asp + Gly162Glu + Tyr171Asp + Tyr210Ala +
Thr217Ser + Ser222Asp
Val115Asp + Tyr210Gln + Ser220Glu + Leu221Asp +
Ser222Asp + Gly223Ser
Ala114His + Asn166Asp + Tyr171Cys + Tyr210Glu +
Ser220Asp + Leu221Asp
Val115Cys + Gly139Asn + Ala164Gly + Pro205Asn +
Thr217Asp + Ser220Asp
Thr167Gln + Tyr210Ile + Thr215Gly + Thr217Asp +
Tyr218Asn + Ser220Asp
Thr137Ser + Trp208Leu + Tyr210Leu + Thr217Glu +
Ser220Asp + Leu221Gly
Thr111Asn + Gly135Ser + Trp208Asp + Tyr210Glu +
Thr217Glu + Leu221Ala
Thr113Asn + Ala114Gly + Thr137Asp + Thr167Asp +
Trp208Gln + Gly223Asn
Ser 70Asp + Thr 73Glu + Asn163Asp + Thr167Pro +
Pro214Glu + Thr217Gly
Gly135Glu + Tyr171Asn + Pro205Gln + Ser207Glu +
Trp208Glu + Ser220Asp
Gly 69Asp + Asp105Glu + Gly108Asp + Ser207Asp +
Trp208Thr + Gly223Asn
Thr113Gly + Ala114Pro + Tyr210Asp + Pro214Asp +
Thr217Gln + Ser220Asp
Asn 68Glu + Ser 70Asp + Asp105Glu + Ala114Thr +
Gly135Ser + Ser220Asp
Thr111Ser + Thr137Glu + Ser207Glu + Trp208Thr +
Ser220Glu + Leu221Asp
Gly 69Asp + Leu104Asp + Asp105Glu + Asn140Glu +
Asn166Ser + Leu221His
Thr137Asp + Gly139Glu + Asn170Glu + Trp208Cys +
Tyr210Asp + Leu221Thr
Gly 67Pro + Trp112Gln + Ser192Asp + Tyr210Ile +
Ser220Asp + Ser222Asp
Val103Gln + Gly108Asp + Gly135Glu + Thr137Glu +
Ala168Gln + Tyr210Asn
Val115Asp + Leu134Glu + Asn166Gln + Asn170Asp +
Tyr210Val + Thr212Pro
Asn 66Asp + Asn 68Ser + Thr167Gln + Ile209Leu +
Ser216Asp + Thr217Glu
Val103G1u + Gly108Asp + Gly110Glu + Gly165Pro +
Thr195Glu + Thr217Gln
Asn 66Asp + Ser 70Glu + Thr 73Asp + Ser109Asp +
Gly136Pro + Tyr210Ile
Gly 69Asp + Ser 70Glu + Asp105Glu + Asn163Glu +
Tyr210Met + Thr217Gln
Asn 68Gln + Leu134Glu + Ser207Asp + Trp208Pro +
Tyr210Asp + Leu221Asp
Asn 66Ser + Val115Gly + Gly162Asp + Ser191Glu +
Trp208Ile + Thr217Ser
Ser 70Glu + Tyr213Thr + Thr217Asn + Tyr218Gly +
Ser222Glu + Gly223Asp
Trp112Met + Gly165Asp + Pro169Ser + Ser207Glu +
Trp208Gly + Ser222Asp
Gly 69Ser + Ser109Asp + Gly110Glu + Ala114Gly +
Gly136Asp + Phe193Asp
Ala164Gln + Gly165Pro + Ser192Asp + Phe193Asp +
Ser207Glu + Thr217Asp
Asn 68Glu + Thr 73Asn + Gly162Gln + Trp208Gln +
Ala219Glu + Ser220Asp
Ser 70Glu + Leu134Ser + Gly165Asp + Asn166Asp +
Ala168Gly + Ile209Gly
Leu104Asp + Asp105Glu + Trp208Gly + Tyr210Glu +
Tyr218Ala + Gly223Pro
Asn 68Asp + Gly 69Glu + Thr111Asn + Trp112His +
Gly136Asn + Pro169Glu
Gly108Ser + Asn140Asp + Ser141Glu + Ala164Gln +
Ser207Glu + Tyr218Ser
Leu104Cys + Gly162Pro + Ser207Glu + Ser216Glu +
Thr217Asp + Ala219Thr
Ala164Asn + Asn166Asp + Gly206Gln + Tyr210Thr +
Ser216Asp + Thr217Asp
Gly108Asp + Ser109Asp + Asn166Ser + Thr217Gln +
Ser220Asp + Leu221Thr
Ser109Asp + Gly110Asp + Val138Ala + Tyr171His +
Ala204His + Ser222Glu
Asn 68Gln + Thr137Gly + Pro169Asp + Ser207Glu +
Trp208Glu + Tyr218Gln
Trp112Asp + Thr113Glu + Val138Gly + Ser191Glu +
Trp208Pro + Leu221Ser
Leu104Gly + Asp105Glu + Asnl06Glu + Gly206Ser +
Trp208His + Tyr218Glu
Gly108Asp + Leu134Asn + Gly136Gln + Trp208Phe +
Ser220Asp + Leu221Asp
Gly108Gln + Trp112Tyr + Asn170Glu + Trp208Gln +
Ser220Glu + Leu221Glu
Gly 72Asn + Asn166Asp + Phe193Ser + Trp208Tyr +
Ser220Glu + Leu221Glu
Asn 66Glu + Gly 67Glu + Thr111Asn + Thr215Gln +
Thr217Asn + Ser220Glu
Asn106Asp + Ser107Asp + Gly165Asp + Phe193Val +
Trp208Val + Leu221Thr
Leu104Val + Gly165Gln + Ser192Asp + Phe193Glu +
Tyr210Glu + Leu221Cys
Gly136Gln + Pro169Ser + Ser192Asp + Phe193Asp +
Trp208Leu + Ser220Glu
Ser107Asp + Val115Thr + Thr137Gln + Gly162Asp +
Asn163Asp + Ala203His
Val103Met + Ser107Glu + Trp208Val + Thr215Glu +
Ser216Glu + Gly223Ser
Val103Ser + Asn140Asp + Ser141Glu + Tyr210Glu +
Ser220Asp + Gly223Asn
Asn163Asp + Asn170Glu + Thr195Asn + Ser207Asp +
Tyr210Met + Tyr218Pro
Asn 66Asp + Gly139Gln + Tyr210Glu + Thr217Ser +
Ser220Asp + Thr224Asn
Gly 69Asp + Asn106Asp + Gly110Asp + Gly165Asn +
Pro169Ser + Thr217Asp
Phe193Ile + Thr215Ser + Thr217Glu + Ser220Asp +
Leu221Pro + Gly223Glu
Val103Gly + Asp105Glu + Thr195Asn + Ser207Asp +
Ser222Asp + Gly223Asn
Gly 69Asp + Asn140Gln + Ala164His + Ala168Ser +
Ser207Asp + Ser222Asp
Asn 68Asp + Thr111Asn + Ala114Gly + Gly135Gln +
Ser207Glu + Ser222Glu
Asn106Asp + Gly139Asn + Gly162Glu + Pro169Ser +
Ser191Asp + Thr224Asp
Thr113Asp + Ser192Asp + Ser207Glu + Tyr213Thr +
Thr215Pro + Ser222Asp
Gly 69Pro + Asn163Asp + Thr195Glu + Trp208Ser +
Tyr210Glu + Leu221Cys
Gly 69Pro + Ser 70Asp + Gly110Ser + Gly135Glu +
Asn170Glu + Leu221Ile
Gly 69Glu + Ala164His + Thr195Gln + Ser220Glu +
Leu221Glu + Thr224Glu
Gly 69Gln + Gly136Asp + Val138Asp + Pro169Gly +
Asn170Gln + Ser220Glu
Gly136Glu + Val138Asp + Thr195Asn + Ser220Glu +
Leu221Gly + Gly223Pro
Asn 68Gln + Ser107Glu + Ser109Glu + Gly139Gln +
Ala164Gln + Ser207Asp
Ser107Glu + Ser109Glu + Pro169Gln + Tyr210Met +
Thr217Pro + Ser222Asp
Gly 67Asp + Ser 70Glu + Val103Ala + Thr111Glu +
Tyr210Asn + Pro214Ser
Asn 66Glu + Gly 67Asp + Leu134His + Ser191Asp +
Ser207Glu + Trp208Thr
Asn 66Glu + Val103Asp + Gly108Asn + Asn170Ser +
Thr217Asn + Leu221Met
Thr 73Glu + Trp112Pro + Asn166Ser + Phe193His +
Tyr218Ile + Ser220Glu
Val115His + Ser207Glu + Trp208Tyr + Tyr210Leu +
Pro214Glu + Leu221Glu
Asn 66Gln + Ser107Glu + Ser109Glu + Ser207Glu +
Gly223Asp + Thr224Gly
Asn 66Glu + Asn 68Asp + Thr 73Gln + Thr195Ser +
Ser207Asp + Tyr218Pro
Ser 70Asp + Leu104Ile + Asn163Asp + Thr217Gln +
Leu221Val + Thr224Glu
Gly 67Asp + Val103Glu + Asn106Asp + Ala168Asn +
Thr195Glu + Trp208Leu
Thr137Gly + Gly162Glu + Phe193Asp + Trp208Asp +
Thr217Asn + Tyr218Val
Gly135Pro + Gly139Glu + Ser207Glu + Trp208Ala +
Tyr210Cys + Gly223Glu
Asn106Ser + Thr137Asp + Gly139Glu + Ser141Asp +
Ala204Gln + Trp208Glu
Trp112Ala + Asn163Glu + Ser192Glu + Trp208Val +
Tyr210Glu + Ser220Glu
Gly110Asp + Trp112Asp + Tyr210Thr + Ser220Glu +
Leu221Met + Ser222Glu
Gly 67Asp + Gly 69Asp + Thr 73Pro + Ser109Asp +
Trp208Gln + Ser222Asp
Asn 66Ser + Val103Glu + Asp105Glu + Trp112His +
Ser191Glu + Tyr210Ala
Gly 67Glu + Gly 69Asn + Gly162Glu + Ser207Glu +
Thr217Asn + Gly223Glu
Ser 70Asp + Gly165Asp + Ala168Asp + Trp208Pro +
Thr217Gly + Leu221Ile
Gly 67Glu + Val103Asn + Gly136Gln + Trp208Pro +
Ser216Glu + Leu221Met
Gly 67Asn + Gly139Glu + Ser141Glu + Tyr213Gly +
Ser220Asp + Leu221Asn
Gly 67Glu + Leu104Ser + Tyr210Ser + Ser220Asp +
Ser222Glu + Gly223Gln
Gly 67Asp + Asn 68Glu + Gly136Asp + Ala168Gln +
Pro169Glu + Phe193Asn
Asn 66Glu + Gly 69Asp + Asn140Gln + Ser192Asp +
Phe193Asp + Tyr210Leu
Leu104Asp + Asn106Glu + Asn170Glu + Tyr210Ile +
Thr215Ser + Thr224Pro
Leu104Asp + Ser107Glu + Gly135Asp + Gly139Asn +
Ala164Glu + Thr217Gly
Trp112Glu + Gly139Glu + Ala164Glu + Thr195Glu +
Thr212Ser + Tyr213Ser
Asn 68Asp + Thr111Gly + Thr113Ser + Val138Asp +
Asn170Asp + Phe193Ser
Asn163Gln + Ala168Asp + Asn170Asp + Ser207Glu +
Thr217Gly + Ser220Asp
Gly 67Asp + Asn106Glu + Thr113Ser + Gly136Gln +
Asn166Glu + Leu221Cys
Asn 66Gln + Gly110Asp + Ala114His + Gly136Glu +
Thr137Asp + Ser222Glu
Gly 67Asp + Asn 68Ser + Gly 72Pro + Gly139Ser +
Thr167Glu + Thr195Asp
Asn 66Asp + Asn 68Gln + Ser191Glu + Ser207Asp +
Trp208Val + Ser220Asp
Ser109Glu + Ala114Glu + Leu134Ile + Gly136Ser +
Ala219Glu + Ser220Asp
Val115Glu + Ala168His + Pro169Asn + Tyr210Asp +
Ser216Glu + Ala219Asp
Asn 66Glu + Asn106Asp + Asnl70Ser + Trp208Thr +
Ser216Asp + Tyr218Gly
Gly162Asn + Asn170Asp + Phe193Glu + Tyr210Gln +
Ser220Glu + Thr224Asp
Gly108Ser + Leu134Pro + Thr137Asp + Pro169Glu +
Ser207Glu + Thr217Gly
Thr137Asp + Val138Glu + Asn163Glu + Ala164Asn +
Ala168Ser + Thr217Glu
Gly162Glu + Trp208Glu + Tyr210Val + Thr217Glu +
Ser220Glu + Gly223Pro
Gly135Asp + Val138Thr + Ser207Asp + Thr217Pro +
Tyr218Ile + Ser220Glu
Leu104Gly + Ser192Asp + Thr195Asp + Thr217Pro +
Ser220Glu + Leu221Asn
Asn 66Ser + Gly136Glu + Val138Glu + Trp208Leu +
Thr217Asp + Ser220Glu
Gly 69Ser + Val103Asp + Ser109Asp + Ser191Asp +
Gly206Gln + Tyr210Pro
Ala114Gly + Gly162Asp + Pro214Gly + Thr215Asp +
Thr217Glu + Ser220Glu
Thr137Gln + Gly139Asp + Gly165Pro + Tyr171Glu +
Thr217Glu + Ser220Glu
Gly 67Glu + Asp105Glu + Asn140Glu + Phe193Gly +
Trp208Leu + Leu221Cys
Leu104Glu + Trp112Leu + Phe193Leu + Ser207Asp +
Trp208Ala + Thr224Asp
Ser 70Glu + Thr113Gly + Gly162Ser + Asn163Asp +
Ala164Glu + Ser220Asp
Gly 69Glu + Ser 70Asp + Thr111Glu + Ser220Asp +
Leu221Pro + Gly223Ser
Asn 66Gln + Leu104Pro + Gly136Glu + Asn163Asp +
Tyr171Ile + Leu221Glu
Ser 70Asp + Leu104Glu + Ala168Asn + Pro169Glu +
Thr195Asp + Trp208Phe
Ser 70Glu + Gly162Glu + Trp208Glu + Thr217Gly +
Leu221Thr + Ser222Asp
Gly 69Asn + Thr137Glu + Gly139Pro + Asn166Asp +
Pro169Asp + Trp208Asp
Gly 69Glu + Leu104Glu + Val115Ser + Asn140Ser +
Ser192Glu + Pro214Asp
Leu104His + Asp105Glu + Val138His + Asn163Asp +
Ser192Glu + Thr217Asn
Ala114Asn + Asn163Glu + Asn170Ser + Ser192Asp +
Ala204Asn + Thr217Asp
Asn 68Gln + Thr 73Asp + Ser109Glu + Trp208Phe +
Pro214Glu + Ser220Asp
Val115Cys + Leu134Asp + Gly135Pro + Ala164Thr +
Asn170Asp + Trp208Asp
Asn 66Glu + Gly 69Glu + Trp112Gln + Gly135Asn +
Gly139Asp + Asn170Glu
Thr 73Gly + Ser107Glu + Gly135Asp + Pro169Asp +
Trp208Thr + Leu221Asn
Gly 67Ser + Ser 70Glu + Gly136Asp + Pro169Asn +
Leu221Asp + Gly223Asp
Ser 70Asp + Gly110Glu + Val138Ser + Tyr210Val +
Leu221Asp + Gly223Asp
Asn 66Asp + Leu104Glu + Ser109Glu + Tyr210Asn +
Thr217Asn + Ser220Asp
Asn 66Glu + Gly 67Asp + Asn163Glu + Ser207Glu +
Thr215Gly + Leu221Thr
Gly 69Glu + Tyr210Glu + Thr215Asp + Thr217Gln +
Tyr218Gln + Ser220Glu
Ser 70Asp + Thr137Glu + Ala164His + Thr167Gly +
Trp208Asp + Ser220Glu
Val138Met + Gly139Gln + Asn140Glu + Ala168Pro +
Tyr171Glu + Thr215Glu
Val103Gly + Asn106Ser + Ser107Asp + Thr111Asp +
Ser222Glu + Gly223Glu
Gly 72Gln + Asn106Glu + Gly110Asp + Thr113Glu +
Gly135Asn + Ala219Glu
Ser109Glu + Thr113Asp + Trp208Ile + Ser220Glu +
Leu221Asp + Thr224Ser
Gly 67Asn + Ser 70Asp + Gly108Asp + Asn170Glu +
Thr215Pro + Leu221Thr
Gly 67Asp + Ser107Asp + Thr167Gly + Tyr210Asn +
Ser220Asp + Ser222Glu
Gly 69Asp + Thr 73Glu + Asn106Gln + Thr111Asn +
Val138Glu + Thr217Asp
Thr111Asn + Ser191Asp + Thr195Asp + Ala204Thr +
Ala219Ser + Ser220Glu
Ser109Asp + Ser191Glu + Tyr210Val + Thr215Asn +
Leu221Gly + Ser222Glu
Thr 73Glu + Leu104Asp + Asn106Gln + Thr195Ser +
Ser207Glu + Ser220Asp
Asn 66Asp + Thr 73Asp + Leu104Glu + Gly136Gln +
Gly162Asp + Leu221Gly
Gly 72Asn + Leu104Asp + Asn163Asp + Tyr171Ser +
Ser191Glu + Thr217Asn
Val115Asp + Gly136Gln + Tyr210Glu + Tyr218Cys +
Leu221Asn + Ser222Asp
Thr 73Asp + Asn140Ser + Asn163Glu + Thr195Asp +
Ser220Asp + Leu221Pro
Asn 68Glu + Leu104Asp + Pro169Asn + Trp208Val +
Thr217Asn + Gly223Glu
Gly110Glu + Thr167Gln + Ser192Glu + Ser207Glu +
Trp208Cys + Ser220Asp
Val103Gly + Gly136Glu + Asn140Asp + Ser207Asp +
Tyr213Asn + Ser220Asp
Thr113Asp + Gly136Asp + Thr137Gln + Asn163Glu +
Asn166Glu + Trp208Phe
Asn 66Glu + Gly 69Glu + Ser109Asp + Ser192Asp +
Phe193Val + Tyr218Ala
Ser 70Glu + Ser141Asp + Asn163Ser + Trp208Met +
Tyr210Pro + Thr215Asp
Asp105Glu + Gly110Asn + Thr111Glu + Leu134Ala +
Ser141Glu + Phe193Tyr
Asn 66Glu + Gly 69Ser + Gly108Asp + Thr111Asp +
Thr195Gly + Tyr210Leu
Gly165Glu + Tyr171Asn + Ser207Glu + Thr215Glu +
Thr217Gly + Thr224Glu
Asn 66Gln + Thr 73Ser + Gly139Asn + Pro214Asp +
Ser220Asp + Leu221Ile
Asn166Glu + Ser192Asp + Trp208Thr + Tyr210Gly +
Thr215Asp + Ser222Glu
Asn 66Asp + Ser191Asp + Thr215Asn + Ala219Asp +
Ser222Asp + Gly223Gln
Asp105Glu + Gly108Glu + Thr195Asn + Ile209Leu +
Pro214Asp + Ser220Asp
Thr111Glu + Val138Asp + Asn163Ser + Tyr218Met +
Leu221Glu + Gly223Asp
Gly 67Glu + Val138Glu + Ser141Glu + Trp208Ile +
Pro214Asn + Thr215Asp
Trpl12Leu + Thr113Gln + Gly165Glu + Thr167Asp +
Thr217Glu + Ser220Asp
Gly 67Gln + Asn 68Asp + Gly 69Asp + Phe193Ala +
Ser216Glu + Ser222Glu
Ser 70Asp + Val115Glu + Gly162Ser + Ala168Thr +
Tyr210Gly + Thr217Asp
Ser 70Asp + Gly136Asn + Gly165Glu + Tyr210Asn +
Thr217Asp + Leu221His
Thr 73Ser + Val103Asn + Ser109Asp + Ser192Asp +
Ser207Asp + Trp208Ile
Asn106Asp + Ser192Glu + Phe193Pro + Ser207Glu +
Thr217Gln + Tyr218Ile
Ser141Asp + Thr167Asp + Ala168Asp + Ser191Asp +
Ala219Asn + Leu221Thr
Asn 66Gln + Ser141Asp + Asn170Ser + Thr217Gln +
Ser220Asp + Gly223Asp
Thr 73Gly + Asp105Glu + Ala114His + Ser220Glu +
Leu221Asn + Gly223Glu
Asn106Asp + Asn140Gln + Trp208Ser + Tyr210Cys +
Ser220Asp + Gly223Glu
Gly 67Gln + Asp105Glu + Ala164Asp + Pro169Asn +
Tyr218Leu + Gly223Asp
Trp112Val + Asn166Asp + Phe193Gly + Pro214Glu +
Ser220Asp + Ser222Glu
Gly108Asp + Thr111Asn + Ser192Glu + Thr217Asn +
Ala219Glu + Ser220Asp
Val103Ser + Val115Asp + Gly139Glu + Asn166Ser +
Ser207Glu + Ser220Glu
Leu104Asp + Asp105Glu + Asn140Glu + Thr167Asp +
Pro214Gly + Ala219Gly
Gly 67Asp + Asn 68Asp + Thr111Asp + Ala164Gln +
Phe193Ser + Ser207Asp
Ser109Glu + Trp208Asp + Ser216Glu + Thr217Asp +
Tyr218Asn + Leu221His
Ser141Asp + Ala168Glu + Tyr210Met + Ser216Glu +
Thr217Asp + Tyr218Ala
Ser109Asp + Gly110Asp + Asn166Asp + Asn170Ser +
Thr215Ser + Leu221Asp
Gly110Glu + Thr167Glu + Ala168Asp + Trp208Met +
Ser220Asp + Thr224Gln
Asp105Glu + Asn106Asp + Gly165Asp + Thr195Ser +
Tyr218Ile + Ser220Asp
Asn106Glu + Ser141Asp + Tyr218Ser + Ala219Thr +
Ser220Asp + Leu221Glu
Thr 73Gln + Thr111Glu + Asn166Asp + Trp208Ser +
Ser220Asp + Leu221Asp
Ser107Glu + Ala168Asn + Pro169Asn + Ser191Asp +
Ser192Asp + Thr217Asp
Ala114Glu + Asn166Ser + Thr212Pro + Thr217Glu +
Tyr218Asp + Thr224Asp
Asn106Glu + Ser107Asp + Gly139Asp + Ala203Asn +
Thr217Ser + Ser220Asp
Thr113Asn + Gly139Ser + Ser141Glu + Thr215Glu +
Ser216Asp + Ser220Asp
Gly 69Gln + Asn140Glu + Gly162Glu + Asn163Asp +
Tyr210Gln + Ser220Asp
Asn 68Asp + Ala114Pro + Gly135Glu + Trp208Asp +
Leu221Ile + Gly223Asp
Asn 68Asp + Ala164Glu + Trp208Cys + Tyr210Glu +
Ala219Thr + Ser220Asp
Thr111Asp + Asn166Asp + Asn170Gln + Tyr210Asp +
Thr212Ser + Ser220Glu
Ser141Glu + Gly165Asp + Trp208Ile + Tyr210Asp +
Thr217Gln + Ser220Asp
Asn 66Gln + Val103Asp + Gly108Pro + Thr137Glu +
Tyr210Glu + Ser220Glu
Gly108Glu + Thr137Gln + Asn163Glu + Tyr210Glu +
Ser220Asp + Leu221Cys
Gly 69Gln + Ser 70Glu + Gly135Glu + Asn163Asp +
Thr217Gly + Ser220Asp
Asn106Glu + Asn140Glu + Asn163Glu + Asn170Glu +
Thr195Asn + Leu221His
Asn106Gln + Asn166Asp + Ala168Asn + Asn170Glu +
Ser207Glu + Ser220Asp
Asn 66Asp + Ser 70Asp + Gly110Gln + Gly136Asp +
Pro214Gln + Ser220Asp
Asn 68Ser + Pro169Asp + Ser192Glu + Ala219Asp +
Gly223Ser + Thr224Asp
Thr 73Pro + Gly135Ser + Phe193Glu + Gly206Gln +
Tyr210Asp + Thr217Glu
Trp112Glu + Val115Gln + Asn170Gln + Thr217Asp +
Tyr218Met + Ser220Asp
Gly110Asn + Val115Glu + Thr137Gln + Ile209Gly +
Thr217Asp + Ser220Glu
Gly108Glu + Thr113Gln + Pro214Asn + Thr217Glu +
Tyr218Gln + Ser220Asp
Gly110Ser + Thr111Gly + Thr113Glu + Phe193Pro +
Thr217Glu + Ser220Asp
Asn166Glu + Trp208Ile + Tyr210Met + Thr217Glu +
Tyr218Val + Ser220Asp
Ser 70Glu + Val103Glu + Val115Gln + Pro169Ser +
Tyr210Ala + Ser220Asp
Asn 66Asp + Ser107Asp + Trp208Met + Tyr210Pro +
Ser220Asp + Ser222Glu
Gly110Ser + Thr111Asp + Gly135Gln + Gly136Asp +
Thr137Asn + Trp208Glu
Thr167Asp + Ala168Ser + Pro169Glu + Trp208Thr +
Thr215Asp + Leu221Asp
Val115Gln + Ala168Gln + Pro169Gln + Phe193Asp +
Tyr210Ser + Leu221Asp
Asn 66Glu + Gly136Pro + Asn140Gln + Ser191Asp +
Trp208Asp + Leu221His
Gly136Glu + Gly139Glu + Ser192Asp + Ala203Asn +
Trp208Asp + Leu221His
Gly 67Asn + Thr113Gln + Thr137Glu + Thr167Asp +
Ala219Gln + Leu221Glu
Gly 69Asn + Thr 73Asp + Thr111Pro + Asn166Asp +
Ser191Asp + Leu221Val
Val138Pro + Asn166Glu + Ser191Asp + Tyr218Asn +
Ser220Asp + Leu221Gln
Asp105Glu + Gly139Asn + Gly165Glu + Trp208Met +
Tyr218Thr + Gly223Asp
Gly110Asn + Thr111Pro + Ala114Asp + Asn170Asp +
Trp208Asp + Tyr210Asp
Gly 67Gln + Gly 69Glu + Ser107Asp + Thr167Glu +
Ala168Asn + Ser207Asp
Gly 69Glu + Gly165Glu + Trp208Cys + Tyr210Cys +
Pro214Asp + Ser220Asp
Ser 70Glu + Gly 72Gln + Val103Thr + Ser109Glu +
Thr113Glu + Ser220Asp
Gly 69Pro + Val115Glu + Tyr210Asn + Ser216Asp +
Ser220Glu + Ser222Glu
Gly136Glu + Trp208Ser + Ser216Asp + Ser220Asp +
Leu221Asn + Ser222Asp
Leu104Glu + Val115Pro + Gly162Ser + Asn166Asp +
Ser220Asp + Ser222Asp
Gly 67Glu + Val138Asp + Thr217Ser + Ser220Asp +
Leu221His + Ser222Asp
Asn 68Asp + Asn170Glu + Gly206Asn + Ser207Asp +
Trp208Ile + Leu221AsP
Asn106Gln + Ser109Glu + Thr113Asp + Leu134Gln +
Thr137Glu + Trp208Asn
Asn106Glu + Gly139Gln + Thr167Glu + Pro169Gln +
Ser191Asp + Ser207Glu
Ser107Glu + Val115Asp + Gly165Asn + Trp208Thr +
Tyr218Asp + Ser220Glu
Gly72Asn + Asn106Gln + Gly139Asp + Pro169Glu +
Trp208Pro + Ser220Glu
Val138Asp + Ser141Glu + Pro169Ser + Ser207Glu +
Ala219Glu + Leu221Thr
Asn106Gln + Ala114Asp + Gly135Asp + Thr195Asn +
Ser207Glu + Ser220Asp
Ser 70Asp + Asn166Glu + Asn170Gln + Ser216Glu +
Thr217Gln + Thr224Gly
Gly 69Asp + Asn140Ser + Gly162Pro + Trp208Gly +
Thr217Glu + Leu221Asp
Asn 68Asp + Ser107Asp + Ala114Gln + Gly162Asp +
Thr217Pro + Ser220Glu
Ser 70Asp + Thr111Asp + Ile209Met + Thr217Gly +
Ser220Glu + Leu221Asn
Ser 70Asp + Leu104His + Thr111Gln + Tyr171Ser +
Phe193Asp + Ser220Glu
Thr113Gly + Gly139Pro + Ser141Glu + Tyr171Glu +
Ser192Asp + Ile209Ser
Trp112Ala + Thr113Glu + Val138Gln + Ser141Asp +
Ser216Asp + Leu221Ser
Gly 69Asn + Asn106Asp + Trp112Gly + Gly162Asp +
Phe193Glu + Ser220Glu
Asn 68Ser + Val103Glu + Asn106Asp + Ala168Pro +
Pro169Asp + Pro214Glu
Leu104Glu + Ala114Ser + Asn140Ser + Gly165Asp +
Ser207Asp + Ser220Glu
Asn 68Asp + Ser109Glu + Gly139Glu + Ala204Ser +
Leu221His + Gly223Asn
Thr111Gly + Val138Pro + Gly139Asp + Ser207Glu +
Ser216Glu + Ser220Asp
Asn106Asp + Asn170Ser + Ser192Glu + Thr195Asp +
Trp208His + Ser220Glu
Asn106Asp + Gly162Asp + Asn166Gln + Thr167Asp +
Pro214Asp + Ala219Thr
Val115Glu + Gly136Glu + Ser207Glu + Tyr218Gly +
Ala219Pro + Leu221Pro
Gly136Ser + Gly162Asp + Asn163Gln + Ala164His +
Ser216Asp + Ser222Glu
Asn 68Ser + Thr 73Glu + Asn166Glu + Asn170Gln +
Tyr171Gly + Leu221Asp
Thr113Glu + Val115Cys + Thr137Glu + Ser191Glu +
Thr217Ser + Thr224Glu
Gly 67Asp + Ser107Asp + Gly139Asp + Gly165Pro +
Thr167Ser + Thr217Glu
Thr73Gly + Gly108Asp + Thr137Glu + Gly162Glu +
Tyr210Gln + Ser220Asp
Leu104Asp + Gly139Pro + Tyr171Asp + Ser191Asp +
Ser222Glu + Thr224Ser
Thr113Asp + Pro169Glu + Tyr210Gln + Pro214Ser +
Ser220Glu + Gly223Asp
Gly108Asp + Gly136Glu + Ser141Asp + Thr195Asp +
Thr215Ser + Thr217Gln
Ser107Asp + Asn163Glu + Pro169Gly + Ser207Asp +
Trp208Asn + Gly223Asn
Gly110Asp + Asn163Asp + Ser191Asp + Thr195Gln +
Tyr210Glu + Thr217Pro
Val103Glu + Gly108Asp + Ala203Gly + Trp208Met +
Ala219Asp + Thr224Glu
Thr73Gln + Thr111Asp + Leu134Asp + Gly136Ser +
Asn163Gln + Ser207Asp
II. Detergent composition
...
In another embodiment of the present invention, one or more enzyme variant bodies of significant quantity are included in and are used for washing the composition that various needs remove the surface of deproteinize dirt.This cleaning composition comprises the unrestricted form cleaning composition (for example, liquid or particle) that is used for washed hardened surface; The cleaning composition (particle, liquid or strip preparation) that is used for the unrestricted form of laundering of textile fabrics; Dish washing compositions (unrestricted form); The oral cavity of unrestricted form cleaning composition (for example, tooth powder, toothpaste and mouth wash shua preparation); The artificial tooth cleaning composition of unrestricted form (for example, liquid, tablet); Contact lens cleaning composition (for example, liquid, tablet) with unrestricted form.
Except the above-mentioned hot enzyme variant body of this paper, cleaning composition also comprises one or more cleaning composition materials compatible with proteolytic enzyme.Term used herein " cleaning composition material " (for example refers to the particular type of selecting to be used for required cleaning composition and product form, liquid, particle, strip, sprays, bar-shaped, paste, gel) any liquid, solid or gaseous material, this material also should be compatible with the hot enzyme variant body that uses in the composition.Surfacing by considering to be washed, the form (for example using by washing composition) that in use is used for composition required under the wash conditions are specifically selected the cleaning composition material at an easy rate.Term used herein " compatible " refers to proteolytic activity that the cleaning composition material do not reduce hot enzyme variant body in the normal use occasion degree that lost efficacy of proteolytic enzyme as required.Concrete cleaning composition material is illustrated in greater detail hereinafter.
" the enzyme variant body of significant quantity " used herein refers to obtaining the amount of the essential enzyme variant body of enzymic activity required in concrete cleaning composition.This significant quantity is easy to be determined by those skilled in the art, and it is based on many factors, and for example used concrete enzyme variant body, washing are used, the concrete composition of cleaning composition and whether need liquid or anhydrous (for example particle, strip) composition or the like.Cleaning composition preferably contains the 0.0001%-that has an appointment about 10% one or more enzyme variant bodies of the present invention, and more preferably from about 0.001%-is about 1%, also preferred about 0.01%-about 0.1%.Wherein use some examples of the various cleaning composition of enzyme variant body to discuss further hereinafter.All umbers used herein, percentage ratio and ratio are by weight, except as otherwise noted.
" non-woven cleaning composition " used herein comprises hard surface detergent compositions, dish washing compositions, oral cavity cleaning composition, artificial tooth cleaning composition and contact lens cleaning composition.A. the cleaning composition that is used for crust, tableware and fabric
Enzyme variant body of the present invention wherein needing in the various cleaning composition of high bubble and efficient insoluble substrate removal can be used for.Therefore, the enzyme variant body can use to provide the hard surface detergent of full preparation, dish washing compositions, fabric cleaning composition or the like with various conventional ingredients.This composition can be liquid, particle, bar form or the like.This composition can be mixed with the modern times of containing nearly by tensio-active agent weight 30%-60% and " concentrate " washing composition.
Cleaning composition of the present invention optionally and preferably contains the tensio-active agent of various negatively charged ion, nonionic, zwitter-ion or the like.These tensio-active agents exist with the content of about 5%-about 35% of composition usually.
The limiting examples that is used for tensio-active agent of the present invention comprises conventional C
11-C
18Alkylbenzene sulfonate and uncle and random alkyl-sulphate, formula are CH
3(CH
2) x (CHOSO
3 -M
+) CH
3And CH
3(CH
2) y (CHOSO
3 -M
+) CH
2CH
3C
10-C
18Secondary (2,3) alkyl-sulphate, x and (y+1) be wherein at least about 7, preferably at least about 9 integer, M is a water-soluble cationic, especially sodium, C
10-C
18Alkyl alkoxy sulfate (especially EO 1-5 ethoxy sulfate), C
10-C
18Alkyl alkoxy carboxylate salt (especially EO 1-5 ethoxy carboxylate), C
10-C
18Alkyl poly glucoside and their corresponding sulfation glycan glycosides, and C
12-C
18α-sulfonated fatty acid ester, C
12-C
18Alkyl and alkylphenol alcoxylates (especially ethoxylate and blended ethoxylate/propoxylated glycerine), C
12-C
18Trimethyl-glycine and sultaine (" sultaines "), C
10-C
18Amine oxide or the like.Preferred alkyl alkoxy sulfate of the present invention (AES) and alkyl alkoxy carboxylate salt (AEC).(according to makers-up's needs, it also is preferred using this tensio-active agent and above-mentioned amine oxide and/or trimethyl-glycine or sultaine surfactant mixtures).Other conventional tensio-active agent that uses is listed in normative document.The tensio-active agent that is particularly useful comprises the C in the people's such as Connor of promulgation on March 16th, 1993 US5194639
10-C
18N-methyl glucose amide (glucamides) is classified this paper reference as.
Various other compositions that are used for cleaning composition can be included in the composition of the present invention, and it comprises other activeconstituents, carrier, solubilizing agent, processing aid, dyestuff or pigment, is used for solvent of liquid formulations or the like.Additionally increase foam if desired, in composition, the content with about 1%-about 10% adds whipping agent, for example C usually
10-C
16Alkylolamide.C
10-C
14Monoethanolamine and diglycollic amide have illustrated the type species of this whipping agent.With above-mentioned height bubble cosurfactant, for example to use this class whipping agent together also be favourable for amine oxide, trimethyl-glycine and sultaine.If desired, the dissolved magnesium salts, for example the content that magnesium chloride, sal epsom or the like can about usually 0.1%-about 2% adds so that additional foaming to be provided.
Liquid detergent compositions of the present invention can contain as the water of carrier and other solvent.Low-molecular-weight uncle or secondary alcohol, for example methyl alcohol, ethanol, propyl alcohol and Virahol suit.Single hydroxyl alcohol is preferred for the solubilising of tensio-active agent, but polyvalent alcohol, and the polyvalent alcohol (for example, 1, ammediol, ethylene glycol, glycerine and 1,2-propylene glycol) that for example contains about 6 carbon atoms of the 2-that has an appointment and about 6 hydroxyls of about 2-also can use.It is about 90% that composition can contain the 5%-that has an appointment, this carrier of typically about 10%-about 50%.
Cleaning composition of the present invention will preferably be mixed with in use and operate with aqueous cleaning, washing water will have the pH of about 6.8-about 11.0, therefore final product is prepared in this scope usually. and the technology of control pH in needed scope comprises uses buffer reagent, alkali, acid or the like, is well known by persons skilled in the art.
When preparation hard surface detergent compositions of the present invention and fabric cleaning composition, the content that the makers-up can about by weight 5%-about 50% uses various auxiliary agents.Typical auxiliary agent comprises 1-10 micron zeolite, multi-carboxylate, for example Citrate trianion and oxygen di-succinate, layered silicate, phosphoric acid salt or the like.Other conventional auxiliary agent is listed in standard recipe.
Equally, the makers-up can be in composition, usually with various other the enzymes of the content use of about 0.001%-1% by weight, for example cellulase, lipase, amylase and proteolytic enzyme.Known various washings and enzyme fabric care in the detergent for washing clothes field.
Various bleaching compounds, for example percarbonate, perborate or the like can be usually be used for said composition with the content of about 1%-about 15% by weight.If desired, said composition can also contain bleach activator, for example tetra acetyl ethylene diamine, nonanoly acyloxy benzene sulfonate or the like, and they also are well known in the prior art.Use content to be generally about by weight 1%-about 10%.
Various dirt release agents, especially negatively charged ion oligomer ester type, various sequestrant, especially amino phosphonates do and ethylenediamine disuccinate, various clay stain remover, especially ethoxylation tetraethylene-pentamine, various dispersion agent, especially polyacrylic ester and polyaspartate, various whitening agent, especially negatively charged ion whitening agent, various froth suppressor, especially the content that silane and secondary alcohol, various fabric softener, especially terre verte or the like can about by weight 1%-about 35% is used for composition.The detailed description that this type of conventional substances is arranged in standard recipe and disclosed patent.
In cleaning composition, also can use enzyme stabilizers.Enzyme stabilizers comprises propylene glycol (preferably about 1%-about 10%), sodium formiate (preferably about 0.1%-about 1%) and calcium formiate (preferably about 0.1%-about 1%).L. hard surface detergent compositions
" hard surface detergent compositions " used herein refers to and is used for washed hardened surface, for example liquid of floor, wall, bathroom tile or the like and particle cleaning composition.Hard surface detergent compositions of the present invention contains one or more enzyme variant bodies of the present invention of significant quantity, and it is about 10% to be preferably about 0.001%-by composition organized enzyme weight, and more preferably from about 0.01%-is about 5%, also preferred about 0.05%-about 1%.Except containing one or more enzyme variant bodies, hard surface detergent compositions contains tensio-active agent and water-soluble chelator usually.Yet, at some special product, in the glass cleaner of for example spraying, be not use tensio-active agent sometimes, because they can produce the membranaceous/striped resistates that remains in glass surface.
When existing, surface active agent composition can contain few to 0.1% of composition, but usually composition will to contain the 0.25%-that has an appointment about 10%, the tensio-active agent of 1%-about 5% more preferably from about.
Composition contains the detergent builder of the 0.5%-that has an appointment about 50% usually, is preferably about 1%-about 10%.
The pH value is preferred in the scope of about 8-12.Regulate if desired, can use conventional pH regulator agent, for example sodium hydroxide, yellow soda ash or hydrochloric acid.
In composition, can comprise solvent.Useful solvent comprises, but be not restricted to, glycol ether, for example Diethylene Glycol list hexyl ether, Diethylene Glycol single-butyl ether, ethylene glycol monobutyl ether, ethylene glycol mono hexyl ether, propylene glycol single-butyl ether, dipropylene glycol single-butyl ether, and glycol, for example 2,2.4-trimethylammonium-1,3-pentanediol and 2-ethyl-1, the 3-hexylene glycol.When using, solvent is about 15% with about 0.5%-usually, the content existence of preferably about 3%-about 11%.
In addition, when composition is applied to can use the high volatile volatile solvent when rinsing is not carried out in surperficial rear surface in composition of the present invention with " fully intensity ", for example Virahol or ethanol are to help composition from surperficial rapid evaporation.When using, volatile solvent is present in the composition with the content of about 2%-about 12% usually.
The embodiment of hard surface detergent compositions of the present invention is by following embodiment explanation.
Embodiment 7-12
The liquid hard-surface cleaning composition
Embodiment component 789 10 11 12Gln66Asn 0.05 0.50 0.02 0.03 0.10 0.03Gly206Asn----0.20 0.02Na
2DIDA
*EDTA
*--2.90 2.90--Trisodium Citrate----2.90 2.90C
12Sodium alkyl benzene sulfonate 1.95-1.95-1.95-C
12Sodium alkyl sulfate-2.20-2.20-2.20C
12(oxyethyl group)
* *Sodium sulfate-2.20-2.20-2.20C
12Dimethyl amine oxide compound-0.50-0.50-0.50 cumene sodium sulfonate 1.30-1.30-1.30-hexyl Trivalin SF
* *6.30 6.30 6.30 6.30 6.30 6.30 water
* * *Balance to 100%
*N-Diethylene Glycol-N, the N-Iminodiacetic acid sodium salt
*Ethylenediamine-N,N'-diacetic acid(EDDA) four sodium
* *Diethylene Glycol list hexyl ether
* * *All prescriptions are adjusted to pH7
In embodiment 7-10, replace Gln66Asn with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
In embodiment 11-12, any combination replacement Gln66Asn and Gly206Asn with hot enzyme variant body listed among the table 2-36 obtain substantially similar result.
Embodiment 13-18
Be used for cleaning of hard surfaces and remove the spray composite that family goes mouldy
Embodiment component 13 14 15 16 17 18Thr111Asn 0.50 0.05 0.60 0.30 0.20 0.30Thr217Gly+Ser222Glu----0.30 0.10 sodium octyl sulfate 2.00 2.00 2.00 2.00 2.00 2.00 lauryl sodium sulfate 4.00 4.00 4.00 4.00 4.00 4.00 NaOH 0.80 0.80 0.80 0.80 0.80 0.80 silicate (sodium) 0.04 0.04 0.04 0.04 0.04 0.04 spices 0.35 0.35 0.35 0.35 0.35 0.35 water balance to 100% product pH are approximately 7.
In embodiment 13-16, replace Thr111Asn with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
In embodiment 17-18, any combination replacement Thr111Asn and Thr217Gly+Ser222Glu with hot enzyme variant body listed among the table 2-36 obtain substantially similar result.
2. dish washing compositions
In another embodiment of the present invention, dish washing compositions contains one or more enzyme variant bodies of the present invention." dish washing compositions " used herein refers to the form of ownership of the composition that is used for wash dining set, and it comprises, but is not restricted to particle and liquid form.The embodiment of dish washing compositions of the present invention is by following embodiment explanation.
Embodiment 19-24
Dish washing compositions
Embodiment component 19 20 21 22 23 24Gly139Asn 0.05 0.50 0.02 0.40 0.10 0.03Ser207Glu+Tyr210Ser----0.40 0.02+Gly223Asn C
12-C
14N-methyl glucose acyl 0.90 0.90 0.90 0.90 0.90 0.90 amine C
12Oxyethyl group (1) vitriol 12.00 12.00 12.00 12.00 12.00 12.002-methyl undecanoic acids 4.50 4.50 4.50 4.50 4.50 4.50C
12Oxyethyl group (2) carboxylate salt 4.50 4.50 4.50 4.50 4.50 4.50C
12Alcohol ethoxylate (4) 3.00 3.00 3.00 3.00 3.00 3.00C
12Amine oxide 3.00 3.00 3.00 3.00 3.00 3.00 cumene sodium sulfonates 2.00 2.00 2.00 2.00 2.00 2.00 ethanol 4.00 4.00 4.00 4.00 4.00 4.00Mg
++(as magnesium chloride) 0.20 0.20 0.20 0.20 0.20 0.20Ca
++(as calcium chloride) 0.40 0.40 0.40 0.40 0.40 0.40 water balance to 100% product pH regulator to 7.
In embodiment 19-22, replace Gly139Asn with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
In embodiment 23-24, any combination replacement Gly139Asn and Ser207Glu+Tyr210Ser+Gly223Asn with hot enzyme variant body listed among the table 2-36 obtain substantially similar result.
3. fabric cleaning composition
In another embodiment of the present invention, fabric cleaning composition contains one or more enzyme variant bodies of the present invention." fabric cleaning composition " used herein refers to the form of ownership of the composition that is used for laundering of textile fabrics, and it comprises, but is not restricted to particle, liquid and bar form.Preferred fabric cleaning composition is a liquid form.A. particle fabric cleaning composition
Particle fabric cleaning composition of the present invention contains one or more enzyme variant bodies of the present invention of significant quantity, and it is about 10% to be preferably about 0.001%-by composition organized enzyme weight, and more preferably from about 0.005%-is about 5%, also preferred about 0.01%-about 1%.Except containing one or more enzyme variant bodies, the particle fabric cleaning composition contain usually at least a tensio-active agent, one or more auxiliary agents and, in some cases, SYNTHETIC OPTICAL WHITNER.
The embodiment of particle fabric cleaning composition of the present invention is by following embodiment explanation.
Embodiment 25-28
The particle fabric cleaning composition
Embodiment component 25 26 27 28Ala168Asn 0.10 0.20 0.03 0.05Tyr210Gly+Thr212Pro+Pro--0.02 0.05214Gly+Ser222AspC
13Linear alkylbenzene sulfonate (LAS) 22.00 22.00 22.00 22.00 phosphate (as sodium phosphate trimer) 23.00 23.00 23.00 23.00 sodium carbonate 23.00 23.00 23.00 23.00 sodium metasilicate 14.00 14.00 14.00 14.00 zeolite 8.20 8.20 8.20 8.20 chelating agent (diethylenetriamine pentaacetic acid) 0.40 0.40 0.40 0.40 sodium sulphate 5.50 5.50 5.50 5.50 water balances to 100%
In embodiment 25-26, replace Ala168Asn with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
In embodiment 27-28, any combination replacement Ala168Asn and Tyr210Gly+Thr212Pro+Pro214Gly+Ser222Asp with hot enzyme variant body listed among the table 2-36 obtain substantially similar result.
Embodiment 29-32
The particle fabric cleaning composition
Embodiment component 29 30 31 32Thr195Pro 0.10 0.20 0.03 0.05Trp208Phe+Tyr213Met+Thr215--0.02 0.05Pro+Ser220Glu+Thr224GlyC
12Sad 4.00 4.00 4.00 4.00C of alkylbenzene sulfonate 12.00 12.00 12.00 12.00 zeolite A (1-10 micron) 26.00 26.00 26.00 26.002-butyl
12-C
14Secondary (2,3) sodium alkyl sulfate 5.00 5.00 5.00 5.00 Trisodium Citrates 5.00 5.00 5.00 5.00 white dyes 0.10 0.10 0.10 0.10 sodium sulfate, 17.00 17.00 17.00 17.00 water and small number of groups balance-dividings to 100%
In embodiment 29-30, replace Thr195Pro with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
In embodiment 31-32, any combination replacement Thr195Pro and Trp208Phe+Tyr213Met+Thr215Pro+Ser220Glu+Thr224Gly with hot enzyme variant body listed among the table 2-36 obtain substantially similar result.
Embodiment 33-36
The particle fabric cleaning composition
Embodiment component 33 34 35 36Gly67Ser+Gly72Ser 0.10 0.20 0.03 0.05Tyr171Thr--0.02 0.05C
13Linear alkylbenzene sulfonate (LAS) 22.00 22.00 22.00 22.00 phosphate (as sodium phosphate trimer) 23.00 23.00 23.00 23.00 sodium carbonate 23.00 23.00 23.00 23.00 sodium metasilicate 14.00 14.00 14.00 14.00 zeolite 8.20 8 20 8.20 8.20 chelating agent (diethylenetriamine pentaacetic acid) 0.40 0.40 0.40 0.40 sodium sulphate 5.50 5.50 5.50 5.50 water balances to 100%
In embodiment 33-34, replace Gly67Ser+Gly72Ser with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
In embodiment 35-36, any combination replacement Gly67Ser+Gly72Ser and Tyr171Thr with hot enzyme variant body listed among the table 2-36 obtain substantially similar result.
Embodiment 37-40
The particle fabric cleaning composition
Embodiment component 37 38 39 40Ser192Asp+Phe193Leu+Thr195As 0.10 0.20 0.03 0.05nTyr213Ser+Thr217Gly+Gly223Glu--0.02 0.05C
12Sad 4.00 4.00 4.00 4.00C of alkylbenzene sulfonate 12.00 12.00 12.00 12.00 zeolite A (1-10 micron) 26.00 26.00 26.00 26002-butyl
12-C
14Secondary (2,3) sodium alkyl sulfate 5.00 5.00 5.00 5.00 Trisodium Citrates 5.00 5.00 5.00 5.00 white dyes 0.10 0.10 0.10 0.10 sodium sulfate, 17.00 17.00 17.00 17.00 water and small number of groups balance-dividings to 100%
In embodiment 37-38, replace Ser192Asp+Phe193Leu+Thr195Asn with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
In embodiment 39-40, any combination replacement Ser192Asp+Phe193Leu+Thr195Asn and Tyr213Ser+Thr217Gly+Gly223Glu with hot enzyme variant body listed among the table 2-36 obtain substantially similar result.
Embodiment 41-42
The particle fabric cleaning composition
Embodiment component 41 42 linear alkylbenzene sulfonates 11.4 10.70 Tallow, beef alkyl-sulphates 1.80 2.40C
14-15Alkyl-sulphate 3.00 3.10C
14-15Polycyclic six mutant
Asn 66Gln + Gly 67Ser + Gly 69Ser + Leu104Gly +
Tyr210Pro + Thr217Glu
Ser 70Asp + Gly110Pro + Gly136Gln + Phe193Ser +
Trp208Cys + Leu221His
Thr113Pro + Gly139Asn + Ser141Glu + Tyr171Pro +
Trp208Thr + Leu221Gly
Gly 69Gln + Leu104Thr + Ser107Asp + Leu134Thr +
Thr215Ser + Leu221Gly
Leu104Met + Leu134Ala + Thr137Asp + Trp208Gly +
Tyr210Val + Pro214Gly
Gly 69Ser + Thr 73Asp + Gly110Ser + Tyr210Leu +
Thr215Gly + Thr217Ser
Asn 66Ser + Gly 72Gln + Thr 73Pro + Gly110Asp +
Trp208Val + Leu221His
Thr111Asn + Ala164His + Thr167Glu + Phe193Met +
Tyr210Asn + Thr217Gln
Asn 66Gln + Thr 73Gly + Thr113Asp + Asn166Ser +
Thr167Pro + Tyr210Pro
Leu104Met + Pro205Gln + Ser207Asp + Trp208Ala +
Thr212Gly + Thr217Pro
Leu134Val + Gly165Gln + Trp208Thr + Pro214Gly +
Leu221Ile + Thr224Asp
Asn 66Ser + Ser109Asp + Ala114Asn + Val115Asn +
Trp208Gln + Tyr210Ser
Asn106Gln + Ala164Pro + Gly165Ser + Tyr171Ala +
Ser220Glu + Thr224Ser
Gly110Ser + Gly136Pro + Ile209His + Thr217Gln +
Leu221Ile + Thr224Asp
Asn 66Gln + Val115Pro + Trp208Asp + Thr217Ser +
Leu221Ile + Thr224Pro
Gly 67Glu + Thr 73Asn + Asn170Ser + Tyr210Ser +
Thr212Gln + Gly223Pro
Val103Gly + Ala164Thr + Tyr210His + Ala219His +
Ser220Glu + Leu221Gly
Thr 73Pro + Asn140Gln + Thr167Asp + Trp208Met +
Thr217Gln + Leu221Asn
Ser109Asp + Ala164His + Tyr210Pro + Thr212Ser +
Gly223Pro + Thr224Asn
Gly110Gln + Tyr210Pro + Tyr213Thr + Tyr218Met +
Ser220Asp + Leu221His
Val138Pro + Ala168Gly + Pro169Gln + Tyr210Ser +
Thr217Gln + Ser220Asp
Ala114Thr + Thr137Asn + Gly139Ser + Trp208Pro +
Pro214Gln + Ser220Glu
Val103Met + Thr137Ser + Ala203Ser + Tyr210Thr +
Leu221Met + Gly223Ser
Leu104Glu + Thr111Ser + Val115His + Gly165Asn +
Tyr210Met + Ala219His
Gly110Pro + Leu134Pro + Asn166Asp + Asn170Ser +
Trp208Asn + Thr217Asn
Thr167Glu + Pro169Gly + Asn170Gln + Trp208Gly +
Thr215Ser + Leu221Ser
Thr111Ser + Thr137Ser + Thr195Gln + Ser207Glu +
Tyr210Val + Thr217Pro
Asn106Asp + Gly136Pro + Gly162Ser + Trp208Ile +
Tyr210Gly + Pro214Gln
Ser 70Asp + Gly165Gln + Phe193Asn + Thr195Ser +
Trp208Pro + Thr212Ser
Gly 72Ser + Ala114Gln + Asn166Gln + Phe193Glu +
Tyr210Gly + Thr224Pro
Asn 66Ser + Gly136Ser + Gly162Pro + Asn163Ser +
Ala164Asp + Ala168Gln
Gly 67Pro + Asn106Gln + Ser191Asp + Trp208His +
Tyr218His + Leu221Asn
Trp112Leu + Ala168Pro + Trp208His + Tyr210Ser +
Thr217Gly + Ser220Asp
Asn 66Ser + Thr111Gly + Val115Gly + Ala168Ser +
Asn170Gln + Pro214Gly
Gly110Ser + Trp112Val + Gly162Asn + Thr167Pro +
Pro169Gln + Ser216Asp
Gly 69Asn + Asn106Ser + Gly139Glu + Asn170Ser +
Tyr210Cys + Leu221Gly
Gly 69Asn + Ser141Asp + Phe193Asn + Tyr210Ile +
Ala219Asn + Leu221Ser
Ser109Asp + Pro169Ser + Trp208His + Pro214Asn +
Thr215Asn + Thr217Gly
Asn 68Asp + Gly162Gln + Ala164His + Trp208Pro +
Tyr210Leu + Leu221Val
Val103Thr + Gly139Pro + Ala164Thr + Thr217Ser +
Leu221Pro + Thr224Pro
Gly 69Glu + Gly 72Gln + Thr137Pro + Trp208Ile +
Tyr218Pro + Gly223Gln
Gly 67Pro + Leu104Cys + Val138Met + Gly139Ser +
Ala203Gln + Ala219Asn
Trp112Ser + Phe193Ala + Thr217Gly + Tyr218Glu +
Leu221Met + Thr224Asn
Asn163Gln + Trp208Leu + Tyr210Ser + Thr217Glu +
Ala219Gly + Gly223Pro
Val103His + Gly110Gln + Gly139Ser + Ser192Asp +
Phe193Asn + Thr217Gln
Gly108Gln + Pro169Asn + Thr195Ser + Trp208Ala +
Thr215Pro + Thr217Glu
Ser109Asp + Thr111Asn + Trp112Gln + Thr167Gln +
Thr195Gly + Tyr210Asn
Gly 72Gln + Trp112Leu + Gly136Asp + Tyr171His +
Tyr210Thr + Leu221Ser
Gly 69Glu + Ala164Pro + Trp208Val + Tyr210Thr +
Tyr218Gln + Thr224Ser
Ala114Pro + Leu134Glu + Asn140Ser + Ala164Gln +
Phe193Ile + Trp208Asn
Asn 66Ser + Val138Met + Gly139Asn + Asn163Gln +
Gly165Gln + Tyr210Thr
Asn106Gln + Ser191Asp + Phe193Leu + Trp208Val +
Pro214Gln + Thr217Ser
Ala114Thr + Asn166Ser + Tyr171Gly + Ser191Glu +
Ala203Pro + Tyr210Ala
Asn 68Gln + Tyr171Asp + Phe193Tyr + Gly206Ser +
Tyr210Val + Leu221Thr
Leu104Ala + Alal14Ser + Asn163Asp + Thr195Gly +
Gly206Gln + Leu221Ala
Gly110Asn + Val115Asn + Trp208Cys + Tyr210His +
Ala219Thr + Gly223Asp
Asn 66Asp + Gly 69Asn + Val115Ala + Ala164Ser +
Trp208Gln + Thr217Gln
Val115Met + Thr137Ser + Gly162Asn + Asn166Glu +
Tyr171His + Pro214Ser
Asn106Gln + Gly110Gln + Trp208His + Thr217Pro +
Ala219Asp + Ser220Asp
Gly 67Asn + Gly 72Asn + Ala114Gly + Asn140Gln +
Ser216Asp + Thr217Asp
Gly 69Gln + Thr 73Ser + Pro169Gln + Trp208Ile +
Ser220Glu + Leu221Asp
Asn170Glu + Tyr171Asp + Phe193Ser + Trp208His +
Leu221Thr + Thr224Gly
Gly 67Ser + Gly 69Glu + Ser 70Glu + Val103Gly +
Tyr210Gln + Ala219Asn
Trp112Gly + Asn166Ser + Trp208Met + Tyr210Glu +
Ser220Glu + Thr224Asn
Leu134Pro + Thr195Gly + Trp208Glu + Tyr210Asp +
Thr217Ser + Ser220Glu
Leu104Gln + Trp112Gln + Tyr171Pro + Trp208Glu +
Thr217Gly + Leu221Glu
Asp105Glu + Gly108Asp + Gly136Gln + Thr167Gln +
Tyr171Gln + Leu221Val
Ser107Glu + Ser109Glu + Val138Met + Ala168His +
Pro169Gln + Phe193Ser
Gly 67Glu + Ser 70Glu + Trp112His + Tyr171Ile +
Trp208His + Tyr210Ala
Val103Pro + Trp208Glu + Tyr210Ser + Ala219Glu +
Ser220Glu + Ser222Asp
Ser191Asp + Ser207Glu + Tyr210Ala + Thr215Gly +
Thr217Gln + Gly223Ser
Asn106Glu + Ser109Asp + Ala168Thr + Tyr171Met +
Phe193Ile + Trp208Leu
Asn 68Ser + Thr137Gln + Ser191Asp + Ser207Asp +
Trp208Asp + Leu221Thr
Val103Gln + Val138His + Asn166Asp + Ser192Glu +
Trp208His + Leu221Gly
Val103Pro + Gly139Pro + Asn163Asp + Gly165Gln +
Ala168Glu + Tyr210Leu
Asn 68Ser + Thrl13Gln + Leu134Ile + Ser191Glu +
Leu221His + Gly223Glu
Gly110Gln + Ser207Glu + Trp208Gln + Thr217Pro +
Tyr218Gly + Ser220Asp
Gly162Ser + Phe193Ala + Trp208Glu + Ile209Ser +
Leu221Cys + Gly223Glu
Ser 70Asp + Asp105Glu + Gly108Glu + Asn140Gln +
Trp208Leu + Thr217Gly
Glyl10Asn + Thr137Glu + Pro169Asp + Asn170Ser +
Thr195Glu + Tyr210His
Asn 68Gln + Gly162Glu + Ala164Thr + Gly165Asp +
Tyr171Ala + Ser192Asp
Val138Met + Gly139Asn + Asn170Gln + Tyr210Glu +
Thr217Asp + Ser220Glu
Gly139Ser + Asn163Asp + Ala164Ser + Ser191Asp +
Tyr210Gly + Leu221Ala
Ser 70Asp + Thr 73Asp + Thr167Ser + Trp208Ser +
Thr217Asp + Ala219Asp
Asn 66Glu + Leu104Glu + Asp105Glu + Ser107Asp +
Leu221Ser + Gly223Pro
Asn 66Glu + Thr 73Asp + Gly110Pro + Ala168Gly +
Tyr218Val + Leu221Ile
Gly 67Asn + Asp105Glu + Asn106Glu + Thr111Glu +
Gly165Asn + Thr217Gly
Asn 66Asp + Tyr210Ser + Pro214Glu + Thr215Asp +
Thr217Gln + Tyr218Asp
Thr 73Asn + Ser192Glu + Ala203Thr + Ser207Asp +
Trp208Glu + Leu221Glu
Val138Gly + Pro169Glu + Ser192Glu + Thr195Glu +
Trp208Pro + Thr212Gln
Thr 73Asp + Gly108Asn + Leu134Ser + Tyr210Ala +
Thr217Gln + Tyr218Glu
Thr 73Asn + Ala114Thr + Val138Ser + Gly139Asp +
Ser141Glu + Asn170Glu
Gly108Gln + Gly135Pro + Gly162Asn + Ser220Glu +
Leu221Ala + Gly223Glu
Val103Gln + Trp112Cys + Ala164Glu + Trp208Gln +
Thr217Gly + Gly223Asp
Thr111Gln + Leu134His + Ser191Asp + Phe193Asp +
Thr195Gln + Trp208Asp
Val103Ser + Leu104Ile + Gly110Glu + Gly136Glu +
Ala164Asn + Tyr210Gln
Leu134Ser + Thr167Gly + Ser191Glu + Ser220Asp +
Leu221Pro + Ser222Asp
Gly 69Gln + Trp208Asp + Pro214Glu + Ser220Asp +
Ser222Glu + Gly223Asn
Ser107Asp + Ser109Glu + Trp112Pro + Gly135Asp +
Ala168Thr + Thr212Gly
Asn140Ser + Thr167Asp + Trp208Glu + Thr217Asn +
Ser220Asp + Leu221Asp
Gly135Asp + Gly162Glu + Tyr171Asp + Tyr210Ala +
Thr217Ser + Ser222Asp
Val115Asp + Tyr210Gln + Ser220Glu + Leu221Asp +
Ser222Asp + Gly223Ser
Ala114His + Asn166Asp + Tyr171Cys + Tyr210Glu +
Ser220Asp + Leu221Asp
Val115Cys + Gly139Asn + Ala164Gly + Pro205Asn +
Thr217Asp + Ser220Asp
Thr167Gln + Tyr210Ile + Thr215Gly + Thr217Asp +
Tyr218Asn + Ser220Asp
Thr137Ser + Trp208Leu + Tyr210Leu + Thr217Glu +
Ser220Asp + Leu221Gly
Thr111Asn + Gly135Ser + Trp208Asp + Tyr210Glu +
Thr217Glu + Leu221Ala
Thr113Asn + Ala114Gly + Thr137Asp + Thr167Asp +
Trp208Gln + Gly223Asn
Ser 70Asp + Thr 73Glu + Asn163Asp + Thr167Pro +
Pro214Glu + Thr217Gly
Gly135Glu + Tyr171Asn + Pro205Gln + Ser207Glu +
Trp208Glu + Ser220Asp
Gly 69Asp + Asp105Glu + Gly108Asp + Ser207Asp +
Trp208Thr + Gly223Asn
Thr113Gly + Ala114Pro + Tyr210Asp + Pro214Asp +
Thr217Gln + Ser220Asp
Asn 68Glu + Ser 70Asp + Asp105Glu + Ala114Thr +
Gly135Ser + Ser220Asp
Thr111Ser + Thr137Glu + Ser207Glu + Trp208Thr +
Ser220Glu + Leu221Asp
Gly 69Asp + Leu104Asp + Asp105Glu + Asn140Glu +
Asn166Ser + Leu221His
Thr137Asp + Gly139Glu + Asn170Glu + Trp208Cys +
Tyr210Asp + Leu221Thr
Gly 67Pro + Trp112Gln + Ser192Asp + Tyr210Ile +
Ser220Asp + Ser222Asp
Val103Gln + Gly108Asp + Gly135Glu + Thr137Glu +
Ala168Gln + Tyr210Asn
Val115Asp + Leu134Glu + Asn166Gln + Asn170Asp +
Tyr210Val + Thr212Pro
Asn 66Asp + Asn 68Ser + Thr167Gln + Ile209Leu +
Ser216Asp + Thr217Glu
Val103G1u + Gly108Asp + Gly110Glu + Gly165Pro +
Thr195Glu + Thr217Gln
Asn 66Asp + Ser 70Glu + Thr 73Asp + Ser109Asp +
Gly136Pro + Tyr210Ile
Gly 69Asp + Ser 70Glu + Asp105Glu + Asn163Glu +
Tyr210Met + Thr217Gln
Asn 68Gln + Leu134Glu + Ser207Asp + Trp208Pro +
Tyr210Asp + Leu221Asp
Asn 66Ser + Val115Gly + Gly162Asp + Ser191Glu +
Trp208Ile + Thr217Ser
Ser 70Glu + Tyr213Thr + Thr217Asn + Tyr218Gly +
Ser222Glu + Gly223Asp
Trp112Met + Gly165Asp + Pro169Ser + Ser207Glu +
Trp208Gly + Ser222Asp
Gly 69Ser + Ser109Asp + Gly110Glu + Ala114Gly +
Gly136Asp + Phe193Asp
Ala164Gln + Gly165Pro + Ser192Asp + Phe193Asp +
Ser207Glu + Thr217Asp
Asn 68Glu + Thr 73Asn + Gly162Gln + Trp208Gln +
Ala219Glu + Ser220Asp
Ser 70Glu + Leu134Ser + Gly165Asp + Asn166Asp +
Ala168Gly + Ile209Gly
Leu104Asp + Asp105Glu + Trp208Gly + Tyr210Glu +
Tyr218Ala + Gly223Pro
Asn 68Asp + Gly 69Glu + Thr111Asn + Trp112His +
Gly136Asn + Pro169Glu
Gly108Ser + Asn140Asp + Ser141Glu + Ala164Gln +
Ser207Glu + Tyr218Ser
Leu104Cys + Gly162Pro + Ser207Glu + Ser216Glu +
Thr217Asp + Ala219Thr
Ala164Asn + Asn166Asp + Gly206Gln + Tyr210Thr +
Ser216Asp + Thr217Asp
Gly108Asp + Ser109Asp + Asn166Ser + Thr217Gln +
Ser220Asp + Leu221Thr
Ser109Asp + Gly110Asp + Val138Ala + Tyr171His +
Ala204His + Ser222Glu
Asn 68Gln + Thr137Gly + Pro169Asp + Ser207Glu +
Trp208Glu + Tyr218Gln
Trp112Asp + Thr113Glu + Val138Gly + Ser191Glu +
Trp208Pro + Leu221Ser
Leu104Gly + Asp105Glu + Asnl06Glu + Gly206Ser +
Trp208His + Tyr218Glu
Gly108Asp + Leu134Asn + Gly136Gln + Trp208Phe +
Ser220Asp + Leu221Asp
Gly108Gln + Trp112Tyr + Asn170Glu + Trp208Gln +
Ser220Glu + Leu221Glu
Gly 72Asn + Asn166Asp + Phe193Ser + Trp208Tyr +
Ser220Glu + Leu221Glu
Asn 66Glu + Gly 67Glu + Thr111Asn + Thr215Gln +
Thr217Asn + Ser220Glu
Asn106Asp + Ser107Asp + Gly165Asp + Phe193Val +
Trp208Val + Leu221Thr
Leu104Val + Gly165Gln + Ser192Asp + Phe193Glu +
Tyr210Glu + Leu221Cys
Gly136Gln + Pro169Ser + Ser192Asp + Phe193Asp +
Trp208Leu + Ser220Glu
Ser107Asp + Val115Thr + Thr137Gln + Gly162Asp +
Asn163Asp + Ala203His
Val103Met + Ser107Glu + Trp208Val + Thr215Glu +
Ser216Glu + Gly223Ser
Val103Ser + Asn140Asp + Ser141Glu + Tyr210Glu +
Ser220Asp + Gly223Asn
Asn163Asp + Asn170Glu + Thr195Asn + Ser207Asp +
Tyr210Met + Tyr218Pro
Asn 66Asp + Gly139Gln + Tyr210Glu + Thr217Ser +
Ser220Asp + Thr224Asn
Gly 69Asp + Asn106Asp + Gly110Asp + Gly165Asn +
Pro169Ser + Thr217Asp
Phe193Ile + Thr215Ser + Thr217Glu + Ser220Asp +
Leu221Pro + Gly223Glu
Val103Gly + Asp105Glu + Thr195Asn + Ser207Asp +
Ser222Asp + Gly223Asn
Gly 69Asp + Asn140Gln + Ala164His + Ala168Ser +
Ser207Asp + Ser222Asp
Asn 68Asp + Thr111Asn + Ala114Gly + Gly135Gln +
Ser207Glu + Ser222Glu
Asn106Asp + Gly139Asn + Gly162Glu + Pro169Ser +
Ser191Asp + Thr224Asp
Thr113Asp + Ser192Asp + Ser207Glu + Tyr213Thr +
Thr215Pro + Ser222Asp
Gly 69Pro + Asn163Asp + Thr195Glu + Trp208Ser +
Tyr210Glu + Leu221Cys
Gly 69Pro + Ser 70Asp + Gly110Ser + Gly135Glu +
Asn170Glu + Leu221Ile
Gly 69Glu + Ala164His + Thr195Gln + Ser220Glu +
Leu221Glu + Thr224Glu
Gly 69Gln + Gly136Asp + Val138Asp + Pro169Gly +
Asn170Gln + Ser220Glu
Gly136Glu + Val138Asp + Thr195Asn + Ser220Glu +
Leu221Gly + Gly223Pro
Asn 68Gln + Ser107Glu + Ser109Glu + Gly139Gln +
Ala164Gln + Ser207Asp
Ser107Glu + Ser109Glu + Pro169Gln + Tyr210Met +
Thr217Pro + Ser222Asp
Gly 67Asp + Ser 70Glu + Val103Ala + Thr111Glu +
Tyr210Asn + Pro214Ser
Asn 66Glu + Gly 67Asp + Leu134His + Ser191Asp +
Ser207Glu + Trp208Thr
Asn 66Glu + Val103Asp + Gly108Asn + Asn170Ser +
Thr217Asn + Leu221Met
Thr 73Glu + Trp112Pro + Asn166Ser + Phe193His +
Tyr218Ile + Ser220Glu
Val115His + Ser207Glu + Trp208Tyr + Tyr210Leu +
Pro214Glu + Leu221Glu
Asn 66Gln + Ser107Glu + Ser109Glu + Ser207Glu +
Gly223Asp + Thr224Gly
Asn 66Glu + Asn 68Asp + Thr 73Gln + Thr195Ser +
Ser207Asp + Tyr218Pro
Ser 70Asp + Leu104Ile + Asn163Asp + Thr217Gln +
Leu221Val + Thr224Glu
Gly 67Asp + Val103Glu + Asn106Asp + Ala168Asn +
Thr195Glu + Trp208Leu
Thr137Gly + Gly162Glu + Phe193Asp + Trp208Asp +
Thr217Asn + Tyr218Val
Gly135Pro + Gly139Glu + Ser207Glu + Trp208Ala +
Tyr210Cys + Gly223Glu
Asn106Ser + Thr137Asp + Gly139Glu + Ser141Asp +
Ala204Gln + Trp208Glu
Trp112Ala + Asn163Glu + Ser192Glu + Trp208Val +
Tyr210Glu + Ser220Glu
Gly110Asp + Trp112Asp + Tyr210Thr + Ser220Glu +
Leu221Met + Ser222Glu
Gly 67Asp + Gly 69Asp + Thr 73Pro + Ser109Asp +
Trp208Gln + Ser222Asp
Asn 66Ser + Val103Glu + Asp105Glu + Trp112His +
Ser191Glu + Tyr210Ala
Gly 67Glu + Gly 69Asn + Gly162Glu + Ser207Glu +
Thr217Asn + Gly223Glu
Ser 70Asp + Gly165Asp + Ala168Asp + Trp208Pro +
Thr217Gly + Leu221Ile
Gly 67Glu + Val103Asn + Gly136Gln + Trp208Pro +
Ser216Glu + Leu221Met
Gly 67Asn + Gly139Glu + Ser141Glu + Tyr213Gly +
Ser220Asp + Leu221Asn
Gly 67Glu + Leu104Ser + Tyr210Ser + Ser220Asp +
Ser222Glu + Gly223Gln
Gly 67Asp + Asn 68Glu + Gly136Asp + Ala168Gln +
Pro169Glu + Phe193Asn
Asn 66Glu + Gly 69Asp + Asn140Gln + Ser192Asp +
Phe193Asp + Tyr210Leu
Leu104Asp + Asn106Glu + Asn170Glu + Tyr210Ile +
Thr215Ser + Thr224Pro
Leu104Asp + Ser107Glu + Gly135Asp + Gly139Asn +
Ala164Glu + Thr217Gly
Trp112Glu + Gly139Glu + Ala164Glu + Thr195Glu +
Thr212Ser + Tyr213Ser
Asn 68Asp + Thr111Gly + Thr113Ser + Val138Asp +
Asn170Asp + Phe193Ser
Asn163Gln + Ala168Asp + Asn170Asp + Ser207Glu +
Thr217Gly + Ser220Asp
Gly 67Asp + Asn106Glu + Thr113Ser + Gly136Gln +
Asn166Glu + Leu221Cys
Asn 66Gln + Gly110Asp + Ala114His + Gly136Glu +
Thr137Asp + Ser222Glu
Gly 67Asp + Asn 68Ser + Gly 72Pro + Gly139Ser +
Thr167Glu + Thr195Asp
Asn 66Asp + Asn 68Gln + Ser191Glu + Ser207Asp +
Trp208Val + Ser220Asp
Ser109Glu + Ala114Glu + Leu134Ile + Gly136Ser +
Ala219Glu + Ser220Asp
Val115Glu + Ala168His + Pro169Asn + Tyr210Asp +
Ser216Glu + Ala219Asp
Asn 66Glu + Asn106Asp + Asnl70Ser + Trp208Thr +
Ser216Asp + Tyr218Gly
Gly162Asn + Asn170Asp + Phe193Glu + Tyr210Gln +
Ser220Glu + Thr224Asp
Gly108Ser + Leu134Pro + Thr137Asp + Pro169Glu +
Ser207Glu + Thr217Gly
Thr137Asp + Val138Glu + Asn163Glu + Ala164Asn +
Ala168Ser + Thr217Glu
Gly162Glu + Trp208Glu + Tyr210Val + Thr217Glu +
Ser220Glu + Gly223Pro
Gly135Asp + Val138Thr + Ser207Asp + Thr217Pro +
Tyr218Ile + Ser220Glu
Leu104Gly + Ser192Asp + Thr195Asp + Thr217Pro +
Ser220Glu + Leu221Asn
Asn 66Ser + Gly136Glu + Val138Glu + Trp208Leu +
Thr217Asp + Ser220Glu
Gly 69Ser + Val103Asp + Ser109Asp + Ser191Asp +
Gly206Gln + Tyr210Pro
Ala114Gly + Gly162Asp + Pro214Gly + Thr215Asp +
Thr217Glu + Ser220Glu
Thr137Gln + Gly139Asp + Gly165Pro + Tyr171Glu +
Thr217Glu + Ser220Glu
Gly 67Glu + Asp105Glu + Asn140Glu + Phe193Gly +
Trp208Leu + Leu221Cys
Leu104Glu + Trp112Leu + Phe193Leu + Ser207Asp +
Trp208Ala + Thr224Asp
Ser 70Glu + Thr113Gly + Gly162Ser + Asn163Asp +
Ala164Glu + Ser220Asp
Gly 69Glu + Ser 70Asp + Thr111Glu + Ser220Asp +
Leu221Pro + Gly223Ser
Asn 66Gln + Leu104Pro + Gly136Glu + Asn163Asp +
Tyr171Ile + Leu221Glu
Ser 70Asp + Leu104Glu + Ala168Asn + Pro169Glu +
Thr195Asp + Trp208Phe
Ser 70Glu + Gly162Glu + Trp208Glu + Thr217Gly +
Leu221Thr + Ser222Asp
Gly 69Asn + Thr137Glu + Gly139Pro + Asn166Asp +
Pro169Asp + Trp208Asp
Gly 69Glu + Leu104Glu + Val115Ser + Asn140Ser +
Ser192Glu + Pro214Asp
Leu104His + Asp105Glu + Val138His + Asn163Asp +
Ser192Glu + Thr217Asn
Ala114Asn + Asn163Glu + Asn170Ser + Ser192Asp +
Ala204Asn + Thr217Asp
Asn 68Gln + Thr 73Asp + Ser109Glu + Trp208Phe +
Pro214Glu + Ser220Asp
Val115Cys + Leu134Asp + Gly135Pro + Ala164Thr +
Asn170Asp + Trp208Asp
Asn 66Glu + Gly 69Glu + Trp112Gln + Gly135Asn +
Gly139Asp + Asn170Glu
Thr 73Gly + Ser107Glu + Gly135Asp + Pro169Asp +
Trp208Thr + Leu221Asn
Gly 67Ser + Ser 70Glu + Gly136Asp + Pro169Asn +
Leu221Asp + Gly223Asp
Ser 70Asp + Gly110Glu + Val138Ser + Tyr210Val +
Leu221Asp + Gly223Asp
Asn 66Asp + Leu104Glu + Ser109Glu + Tyr210Asn +
Thr217Asn + Ser220Asp
Asn 66Glu + Gly 67Asp + Asn163Glu + Ser207Glu +
Thr215Gly + Leu221Thr
Gly 69Glu + Tyr210Glu + Thr215Asp + Thr217Gln +
Tyr218Gln + Ser220Glu
Ser 70Asp + Thr137Glu + Ala164His + Thr167Gly +
Trp208Asp + Ser220Glu
Val138Met + Gly139Gln + Asn140Glu + Ala168Pro +
Tyr171Glu + Thr215Glu
Val103Gly + Asn106Ser + Ser107Asp + Thr111Asp +
Ser222Glu + Gly223Glu
Gly 72Gln + Asn106Glu + Gly110Asp + Thr113Glu +
Gly135Asn + Ala219Glu
Ser109Glu + Thr113Asp + Trp208Ile + Ser220Glu +
Leu221Asp + Thr224Ser
Gly 67Asn + Ser 70Asp + Gly108Asp + Asn170Glu +
Thr215Pro + Leu221Thr
Gly 67Asp + Ser107Asp + Thr167Gly + Tyr210Asn +
Ser220Asp + Ser222Glu
Gly 69Asp + Thr 73Glu + Asn106Gln + Thr111Asn +
Val138Glu + Thr217Asp
Thr111Asn + Ser191Asp + Thr195Asp + Ala204Thr +
Ala219Ser + Ser220Glu
Ser109Asp + Ser191Glu + Tyr210Val + Thr215Asn +
Leu221Gly + Ser222Glu
Thr 73Glu + Leu104Asp + Asn106Gln + Thr195Ser +
Ser207Glu + Ser220Asp
Asn 66Asp + Thr 73Asp + Leu104Glu + Gly136Gln +
Gly162Asp + Leu221Gly
Gly 72Asn + Leu104Asp + Asn163Asp + Tyr171Ser +
Ser191Glu + Thr217Asn
Val115Asp + Gly136Gln + Tyr210Glu + Tyr218Cys +
Leu221Asn + Ser222Asp
Thr 73Asp + Asn140Ser + Asn163Glu + Thr195Asp +
Ser220Asp + Leu221Pro
Asn 68Glu + Leu104Asp + Pro169Asn + Trp208Val +
Thr217Asn + Gly223Glu
Gly110Glu + Thr167Gln + Ser192Glu + Ser207Glu +
Trp208Cys + Ser220Asp
Val103Gly + Gly136Glu + Asn140Asp + Ser207Asp +
Tyr213Asn + Ser220Asp
Thr113Asp + Gly136Asp + Thr137Gln + Asn163Glu +
Asn166Glu + Trp208Phe
Asn 66Glu + Gly 69Glu + Ser109Asp + Ser192Asp +
Phe193Val + Tyr218Ala
Ser 70Glu + Ser141Asp + Asn163Ser + Trp208Met +
Tyr210Pro + Thr215Asp
Asp105Glu + Gly110Asn + Thr111Glu + Leu134Ala +
Ser141Glu + Phe193Tyr
Asn 66Glu + Gly 69Ser + Gly108Asp + Thr111Asp +
Thr195Gly + Tyr210Leu
Gly165Glu + Tyr171Asn + Ser207Glu + Thr215Glu +
Thr217Gly + Thr224Glu
Asn 66Gln + Thr 73Ser + Gly139Asn + Pro214Asp +
Ser220Asp + Leu221Ile
Asn166Glu + Ser192Asp + Trp208Thr + Tyr210Gly +
Thr215Asp + Ser222Glu
Asn 66Asp + Ser191Asp + Thr215Asn + Ala219Asp +
Ser222Asp + Gly223Gln
Asp105Glu + Gly108Glu + Thr195Asn + Ile209Leu +
Pro214Asp + Ser220Asp
Thr111Glu + Val138Asp + Asn163Ser + Tyr218Met +
Leu221Glu + Gly223Asp
Gly 67Glu + Val138Glu + Ser141Glu + Trp208Ile +
Pro214Asn + Thr215Asp
Trpl12Leu + Thr113Gln + Gly165Glu + Thr167Asp +
Thr217Glu + Ser220Asp
Gly 67Gln + Asn 68Asp + Gly 69Asp + Phe193Ala +
Ser216Glu + Ser222Glu
Ser 70Asp + Val115Glu + Gly162Ser + Ala168Thr +
Tyr210Gly + Thr217Asp
Ser 70Asp + Gly136Asn + Gly165Glu + Tyr210Asn +
Thr217Asp + Leu221His
Thr 73Ser + Val103Asn + Ser109Asp + Ser192Asp +
Ser207Asp + Trp208Ile
Asn106Asp + Ser192Glu + Phe193Pro + Ser207Glu +
Thr217Gln + Tyr218Ile
Ser141Asp + Thr167Asp + Ala168Asp + Ser191Asp +
Ala219Asn + Leu221Thr
Asn 66Gln + Ser141Asp + Asn170Ser + Thr217Gln +
Ser220Asp + Gly223Asp
Thr 73Gly + Asp105Glu + Ala114His + Ser220Glu +
Leu221Asn + Gly223Glu
Asn106Asp + Asn140Gln + Trp208Ser + Tyr210Cys +
Ser220Asp + Gly223Glu
Gly 67Gln + Asp105Glu + Ala164Asp + Pro169Asn +
Tyr218Leu + Gly223Asp
Trp112Val + Asn166Asp + Phe193Gly + Pro214Glu +
Ser220Asp + Ser222Glu
Gly108Asp + Thr111Asn + Ser192Glu + Thr217Asn +
Ala219Glu + Ser220Asp
Val103Ser + Val115Asp + Gly139Glu + Asn166Ser +
Ser207Glu + Ser220Glu
Leu104Asp + Asp105Glu + Asn140Glu + Thr167Asp +
Pro214Gly + Ala219Gly
Gly 67Asp + Asn 68Asp + Thr111Asp + Ala164Gln +
Phe193Ser + Ser207Asp
Ser109Glu + Trp208Asp + Ser216Glu + Thr217Asp +
Tyr218Asn + Leu221His
Ser141Asp + Ala168Glu + Tyr210Met + Ser216Glu +
Thr217Asp + Tyr218Ala
Ser109Asp + Gly110Asp + Asn166Asp + Asn170Ser +
Thr215Ser + Leu221Asp
Gly110Glu + Thr167Glu + Ala168Asp + Trp208Met +
Ser220Asp + Thr224Gln
Asp105Glu + Asn106Asp + Gly165Asp + Thr195Ser +
Tyr218Ile + Ser220Asp
Asn106Glu + Ser141Asp + Tyr218Ser + Ala219Thr +
Ser220Asp + Leu221Glu
Thr 73Gln + Thr111Glu + Asn166Asp + Trp208Ser +
Ser220Asp + Leu221Asp
Ser107Glu + Ala168Asn + Pro169Asn + Ser191Asp +
Ser192Asp + Thr217Asp
Ala114Glu + Asn166Ser + Thr212Pro + Thr217Glu +
Tyr218Asp + Thr224Asp
Asn106Glu + Ser107Asp + Gly139Asp + Ala203Asn +
Thr217Ser + Ser220Asp
Thr113Asn + Gly139Ser + Ser141Glu + Thr215Glu +
Ser216Asp + Ser220Asp
Gly 69Gln + Asn140Glu + Gly162Glu + Asn163Asp +
Tyr210Gln + Ser220Asp
Asn 68Asp + Ala114Pro + Gly135Glu + Trp208Asp +
Leu221Ile + Gly223Asp
Asn 68Asp + Ala164Glu + Trp208Cys + Tyr210Glu +
Ala219Thr + Ser220Asp
Thr111Asp + Asn166Asp + Asn170Gln + Tyr210Asp +
Thr212Ser + Ser220Glu
Ser141Glu + Gly165Asp + Trp208Ile + Tyr210Asp +
Thr217Gln + Ser220Asp
Asn 66Gln + Val103Asp + Gly108Pro + Thr137Glu +
Tyr210Glu + Ser220Glu
Gly108Glu + Thr137Gln + Asn163Glu + Tyr210Glu +
Ser220Asp + Leu221Cys
Gly 69Gln + Ser 70Glu + Gly135Glu + Asn163Asp +
Thr217Gly + Ser220Asp
Asn106Glu + Asn140Glu + Asn163Glu + Asn170Glu +
Thr195Asn + Leu221His
Asn106Gln + Asn166Asp + Ala168Asn + Asn170Glu +
Ser207Glu + Ser220Asp
Asn 66Asp + Ser 70Asp + Gly110Gln + Gly136Asp +
Pro214Gln + Ser220Asp
Asn 68Ser + Pro169Asp + Ser192Glu + Ala219Asp +
Gly223Ser + Thr224Asp
Thr 73Pro + Gly135Ser + Phe193Glu + Gly206Gln +
Tyr210Asp + Thr217Glu
Trp112Glu + Val115Gln + Asn170Gln + Thr217Asp +
Tyr218Met + Ser220Asp
Gly110Asn + Val115Glu + Thr137Gln + Ile209Gly +
Thr217Asp + Ser220Glu
Gly108Glu + Thr113Gln + Pro214Asn + Thr217Glu +
Tyr218Gln + Ser220Asp
Gly110Ser + Thr111Gly + Thr113Glu + Phe193Pro +
Thr217Glu + Ser220Asp
Asn166Glu + Trp208Ile + Tyr210Met + Thr217Glu +
Tyr218Val + Ser220Asp
Ser 70Glu + Val103Glu + Val115Gln + Pro169Ser +
Tyr210Ala + Ser220Asp
Asn 66Asp + Ser107Asp + Trp208Met + Tyr210Pro +
Ser220Asp + Ser222Glu
Gly110Ser + Thr111Asp + Gly135Gln + Gly136Asp +
Thr137Asn + Trp208Glu
Thr167Asp + Ala168Ser + Pro169Glu + Trp208Thr +
Thr215Asp + Leu221Asp
Val115Gln + Ala168Gln + Pro169Gln + Phe193Asp +
Tyr210Ser + Leu221Asp
Asn 66Glu + Gly136Pro + Asn140Gln + Ser191Asp +
Trp208Asp + Leu221His
Gly136Glu + Gly139Glu + Ser192Asp + Ala203Asn +
Trp208Asp + Leu221His
Gly 67Asn + Thr113Gln + Thr137Glu + Thr167Asp +
Ala219Gln + Leu221Glu
Gly 69Asn + Thr 73Asp + Thr111Pro + Asn166Asp +
Ser191Asp + Leu221Val
Val138Pro + Asn166Glu + Ser191Asp + Tyr218Asn +
Ser220Asp + Leu221Gln
Asp105Glu + Gly139Asn + Gly165Glu + Trp208Met +
Tyr218Thr + Gly223Asp
Gly110Asn + Thr111Pro + Ala114Asp + Asn170Asp +
Trp208Asp + Tyr210Asp
Gly 67Gln + Gly 69Glu + Ser107Asp + Thr167Glu +
Ala168Asn + Ser207Asp
Gly 69Glu + Gly165Glu + Trp208Cys + Tyr210Cys +
Pro214Asp + Ser220Asp
Ser 70Glu + Gly 72Gln + Val103Thr + Ser109Glu +
Thr113Glu + Ser220Asp
Gly 69Pro + Val115Glu + Tyr210Asn + Ser216Asp +
Ser220Glu + Ser222Glu
Gly136Glu + Trp208Ser + Ser216Asp + Ser220Asp +
Leu221Asn + Ser222Asp
Leu104Glu + Val115Pro + Gly162Ser + Asn166Asp +
Ser220Asp + Ser222Asp
Gly 67Glu + Val138Asp + Thr217Ser + Ser220Asp +
Leu221His + Ser222Asp
Asn 68Asp + Asn170Glu + Gly206Asn + Ser207Asp +
Trp208Ile + Leu221AsP
Asn106Gln + Ser109Glu + Thr113Asp + Leu134Gln +
Thr137Glu + Trp208Asn
Asn106Glu + Gly139Gln + Thr167Glu + Pro169Gln +
Ser191Asp + Ser207Glu
Ser107Glu + Val115Asp + Gly165Asn + Trp208Thr +
Tyr218Asp + Ser220Glu
Gly72Asn + Asn106Gln + Gly139Asp + Pro169Glu +
Trp208Pro + Ser220Glu
Val138Asp + Ser141Glu + Pro169Ser + Ser207Glu +
Ala219Glu + Leu221Thr
Asn106Gln + Ala114Asp + Gly135Asp + Thr195Asn +
Ser207Glu + Ser220Asp
Ser 70Asp + Asn166Glu + Asn170Gln + Ser216Glu +
Thr217Gln + Thr224Gly
Gly 69Asp + Asn140Ser + Gly162Pro + Trp208Gly +
Thr217Glu + Leu221Asp
Asn 68Asp + Ser107Asp + Ala114Gln + Gly162Asp +
Thr217Pro + Ser220Glu
Ser 70Asp + Thr111Asp + Ile209Met + Thr217Gly +
Ser220Glu + Leu221Asn
Ser 70Asp + Leu104His + Thr111Gln + Tyr171Ser +
Phe193Asp + Ser220Glu
Thr113Gly + Gly139Pro + Ser141Glu + Tyr171Glu +
Ser192Asp + Ile209Ser
Trp112Ala + Thr113Glu + Val138Gln + Ser141Asp +
Ser216Asp + Leu221Ser
Gly 69Asn + Asn106Asp + Trp112Gly + Gly162Asp +
Phe193Glu + Ser220Glu
Asn 68Ser + Val103Glu + Asn106Asp + Ala168Pro +
Pro169Asp + Pro214Glu
Leu104Glu + Ala114Ser + Asn140Ser + Gly165Asp +
Ser207Asp + Ser220Glu
Asn 68Asp + Ser109Glu + Gly139Glu + Ala204Ser +
Leu221His + Gly223Asn
Thr111Gly + Val138Pro + Gly139Asp + Ser207Glu +
Ser216Glu + Ser220Asp
Asn106Asp + Asn170Ser + Ser192Glu + Thr195Asp +
Trp208His + Ser220Glu
Asn106Asp + Gly162Asp + Asn166Gln + Thr167Asp +
Pro214Asp + Ala219Thr
Val115Glu + Gly136Glu + Ser207Glu + Tyr218Gly +
Ala219Pro + Leu221Pro
Gly136Ser + Gly162Asp + Asn163Gln + Ala164His +
Ser216Asp + Ser222Glu
Asn 68Ser + Thr 73Glu + Asn166Glu + Asn170Gln +
Tyr171Gly + Leu221Asp
Thr113Glu + Val115Cys + Thr137Glu + Ser191Glu +
Thr217Ser + Thr224Glu
Gly 67Asp + Ser107Asp + Gly139Asp + Gly165Pro +
Thr167Ser + Thr217Glu
Thr73Gly + Gly108Asp + Thr137Glu + Gly162Glu +
Tyr210Gln + Ser220Asp
Leu104Asp + Gly139Pro + Tyr171Asp + Ser191Asp +
Ser222Glu + Thr224Ser
Thr113Asp + Pro169Glu + Tyr210Gln + Pro214Ser +
Ser220Glu + Gly223Asp
Gly108Asp + Gly136Glu + Ser141Asp + Thr195Asp +
Thr215Ser + Thr217Gln
Ser107Asp + Asn163Glu + Pro169Gly + Ser207Asp +
Trp208Asn + Gly223Asn
Gly110Asp + Asn163Asp + Ser191Asp + Thr195Gln +
Tyr210Glu + Thr217Pro
Val103Glu + Gly108Asp + Ala203Gly + Trp208Met +
Ala219Asp + Thr224Glu
Thr73Gln + Thr111Asp + Leu134Asp + Gly136Ser +
Asn163Gln + Ser207Asp
II. Detergent composition
...
Embodiment 43-44
The particle fabric cleaning composition
Embodiment component 43 44 straight chain C
12Sodium alkyl benzene sulfonate 6.5 8.0 sodium sulphate 15.0 18.0 zeolite A 26.0 22.0 sodium nitrilo triacetate 5.0 5.0 polyvinylpyrrolidone 0.5 0.7 tetra acetyl ethylene diamine 3.0 3.0 boric acid 4.0-perborate 0.5 1 phenolsulfonate 0.1 0.2Pro205Gly+Trp208Leu+Thr217Gln+Leu 0.4 0.4221Gln+Gly223Gln+Thr224Glu filler (for example, silicate; Carbonate; Spices; Water) to 100 to 100
Embodiment 45
Die mould particle fabric cleaning composition composition weight % alkyl-sulphate 8.0 alkyl ethoxy sulfate 2.0C
25And C
45Mixture 6.0 polyhydroxy fatty acid acid amides 2.5 zeolite 17.0 phyllosilicates/citrate 16.0 carbonate 7.0 maleic acid acrylic copolymer 5.0 dirts of 3 and 7 times of ethoxylations of alcohol are freed polymer 0.4 poly-(4-vinylpridine)-N-oxide 0.1 vinyl imidazole of carboxymethyl cellulose 0.4 and vinyl pyrrolidone copolymer 0.1PEG2000 0.2Asn66Ser+Ser70Glu+Gly72Asn 0.5 lipase 0.2 cellulase 0.2 tetra acetyl ethylene diamine 6.0 percarbonate 22.0 EDDS 0.3 foams in hibitors 3.54; 4 '-two (2-morpholinyl-4-anilino--s-triazine-6-base is amino) 0.25 stilbene-2; 2 '-disulfonic acid disodium 4,4 '-two (2-sulphophenyl vinyl) biphenyl disodium 0.05 water, spices and a small amount of component to 100
Embodiment 46
Particle fabric cleaning composition composition weight % linear alkylbenzene sulfonate 7.6C
16-C
18Alkyl-sulphate 1.3C
14-157 times of ethoxylates of alcohol, the 4.0 coconut alkyl dimethyl hydroxyl ethyl ammonium chloride 1.4 dispersant 0.07 siloxanes liquid 0.8 trisodium citrate 5.0 zeolite 4A 15.0 inferior second triamine of maleic acid acrylic copolymer 4.0 2 pentamethylene phosphonic acids 0.4 perborate 15.0 tetra acetyl ethylene diamine 5.0 terre vertes 10.0 poly-(oxirane) are 0.3Ser109Glu+Thr113Gly 0.4 lipase 0.2 amylase 0.3 cellulase 0.2 sodium metasilicate 3.0 sodium carbonate 10.0 carboxymethyl cellulose 0.2 brightening agent 0.2 water, spices and a small amount of component to 100 (MW300000)
Embodiment 47 particle fabric cleaning composition composition weight % linear alkylbenzene sulfonates 6.92 Tallow, beef alkyl-sulphate 2.05C
14-157 times of ethoxylate 4.4C of alcohol
12-15times ethoxylation 0.16 zeolite 20.2 citrate 5.5 carbonate 15.4 silicate 3.4 maleic acid acrylic copolymer 4.0 carboxymethyl cellulose enzyme 0.31 dirts in alkyl ethoxy sulfate-3 are freed the polymer 0.30Gly135Gln+Val138Asp+Gly139Ser 0.20 lipase 0.36 cellulase 0.13 perborate tetrahydrate 11.64 perborate monohydrate 8.7 inferior second triamine of tetra acetyl ethylene diamine 5.0 2 pentamethyl phosphonic acids 0.38 magnesium sulfate 0.40 brightening agent 0.19 spices, siloxanes, the a small amount of component of foam in hibitors 0.85 is to 100b. liquid fabric washing composition
Liquid fabric cleaning composition of the present invention contains one or more enzyme variant bodies of the present invention of significant quantity, and it is about 5% to be preferably about 0.005%-by composition organized enzyme weight, more preferably about 0.01%-about 1%.This liquid fabric cleaning composition also contains a kind of anion surfactant, lipid acid, water soluble detergent auxiliary agent and water usually.
The embodiment of liquid fabric cleaning composition of the present invention is by following embodiment explanation.
Embodiment 48-52
The liquid fabric cleaning composition
Embodiment component 48 49 50 51 52Asn166Asp+Thr167Asn+ 0.05 0.03 0.30 0.03 0.10Asn170Ser+Tyr171ThrSer191Glu+Ser192Asp+---0.01 0.20Phe193Asp+Thr195ProC
12-C
14Sad 5.00 5.00 5.00 5.00 5.00 Trisodium Citrates of sodium alkyl sulfate 20.00 20.00 20.00 20.00 20.002-butyl 1.00 1.00 1.00 1.00 1.00C
10Alcohol ethoxylate (3) 13.00 13.00 13.00 13.00 13.00 monoethanolamines 2.50 2.50 2.50 2.50 2.50 water/propylene glycol/ethanol (100: 1: 1) balances to 100%
In embodiment 48-50, the hot enzyme variant body listed with table 2-36 replaces Asn166Asp+Thr167Asn+Asn170Ser+Tyr171Thr, obtains substantially similar result.
In embodiment 51-52, any combination replacement Asn166Asp+Thr167Asn+Asn170Ser+Tyr171Thr and Ser191Glu+Ser192Asp+Phe193Asp+Thr195Pro with hot enzyme variant body listed among the table 2-36 obtain substantially similar result.
Embodiment 53-57
The liquid fabric cleaning composition
Embodiment component 53 54 55 56 57Pro205Gln+Gly206Ser+Trp208V 0.05 0.03 0.30 0.03 0.10al+Tyr210Leu+Thr212Asn+Tyr218Met+Ser220GluAsn68Asp+V al138Asp+Ala164---0.01 0.20Gly+Ala168Glu+Thr217GlyC
12-C
14Sad 5.00 5.00 5.00 5.00 5.00 Trisodium Citrates of sodium alkyl sulfate 20.00 20.00 20.00 20.00 20.002-butyl 1.00 1.00 1.00 1.00 1.00C
10Alcohol ethoxylate (3) 13.00 13.00 13.00 13.00 13.00 monoethanolamines 2.50 2.50 2.50 2.50 2.50 water/propylene glycol/ethanol (100: 1: 1) balances to 100%
In embodiment 53-55, replace Pro205Gln+Gly206Ser+Trp208Val+Tyr210Leu+Thr212Asn+Tyr218 Met+Ser220Glu with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
In embodiment 56-57, any combination with hot enzyme variant body listed among the table 2-36 replaces Pro205Gln+Gly206Ser+Trp208Val+Tyr210Leu+Thr212Asn+Tyr218 Met+Ser220Glu and Asn68Asp+Val138Asp+Ala164Gly+Ala168Glu+Thr217Gly, obtains substantially similar result.
Embodiment 58-59
The liquid fabric cleaning composition
Embodiment component 58 59C
12-14Alkenyl succinic acid 3.0 8.0 citric acid monohydrate 10.0 15.0C
12-15Sodium alkyl sulfate 8.0 8.0C
12-152 times of ethoxylation sodium sulfate-3.0C of alcohol
12-157 times of ethoxylate-8.0C of alcohol
12-15Alcohol 5 times of inferior second triamines five of ethoxylate 8.0-two (methylene phosphonic acid) 0.2-oleic acid 1.8-ethanol 4.0 4.0 propane diols 2.0 2.0Leu134Cys+Thr137Glu+Val138Gly 0.2 02 polyvinylpyrrolidone 1.0 2.0 foam in hibitors 0.15 0.15 NaOH are to pH7.5 perborate 0.5 1 phenolsulfonate 0.1 0.2 peroxidase 0.4 0.1 water and a small amount of component to 100 part
In embodiment 58 and 59, replace Leu134Cys+Thr137Glu+Val138Gly with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
Embodiment 60-62
The liquid fabric cleaning composition
Example component 606162 citric acids 2.00-2.00 7.10 3.00 3.00 1.93 3.20 3.20 Ethanol 2.22 3.50 3.50 monoethanolamine borate 0.71 1.09 1.091,2 - propylene glycol 7.89 8.00 8.00 1.80 3.00 3.00 cumene sulfonate Sodium hydroxide 0.08 0.08 0.08 silicone defoamer 6.70 3.80 3.80 sodium 1.16 1.18 1.18Gly67Glu Ser70Asp Gly72Ser Thr73Ser 0.0145 - Ile209Ala Ala219Pro-0.0145-Leu216Asn - 0.0145 0.200 0.200 0.200 lipase cellulase soil release polymer -7.50 7.50 0.29 0.06 0.15 0.15 defoamer brightener 36 0.085 0.085 0.095 - brighteners 3-0.05 0.05C12Alkyl benzene sulphonate (ABS) 9.86--C
12-15The many ethoxylations of alkyl (2.5) vitriol 13.80 18.00 18.00C
12Glucamide-5.00 5.00C
12-13Alkyl polyethoxylated (9) 2.00 2.00 2.00 water, spices and small number of groups balance-dividing are to 100%c. strip fabrics cleaning composition
The strip fabrics cleaning composition that is suitable for hand-washing dirty fabric of the present invention contains one or more enzyme variant bodies of the present invention of significant quantity, and it is about 10% to be preferably about 0.001%-by composition organized enzyme weight, more preferably about 0.01%-about 1%.
The embodiment of strip fabrics cleaning composition of the present invention is by following embodiment explanation.
Embodiment 63-66
The strip fabrics cleaning composition
Embodiment component 63 64 65 66Trp112Cys+Thr217Gly 0.3-0.1 0.02Val103Ala+Thr212Ser--0.4 0.03C
12-C
16Sodium alkyl sulfate 20.0 20.0 20.0 20.00C
12-C
14N-methyl glucose amide 5.0 5.0 5.0 5.00C
11-C
13Sodium alkyl benzene sulfonate 10.0 10.0 10.0 10.00 sodium carbonate 25.0 25.0 25.0 25.00 sodium pyrophosphate 7.0 7.0 7.0 7.00 sodium phosphate trimer 7.0 7.0 7.0 7.00 zeolite A (0.1-10 μ) 5.0 5.0 5.0 5.00 carboxymethyl cellulose 0.2 0.2 0.2 0.20 polyacrylate (MW1400) 0.2 0.2 0.2 0.20 coconut alkyl MEA 5.0 5.0 5.0 5.00 brightening agents, spices 0.2 0.2 0.2 0.20 calcium sulfate 1.0 1.0 1.0 1.00 magnesium sulfate 1.0 1.0 1.0 1.00 water 4.0 4.0 4.0 4.00 fillers*Balance to 100%
*Can be selected from conventional material, for example lime carbonate, talcum, clay, silicate or the like.
In embodiment 63-64, replace Trp112Cys+Thr217Gly with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
In embodiment 65-66, any combination replacement Trp112Cys+Thr217Gly and Val103Ala+Thr212Ser with hot enzyme variant body listed among the table 2-36 obtain substantially similar result.
Embodiment 67-70
The strip fabrics cleaning composition
Embodiment component 67 68 69 70Ser109Glu 0.3-0.1 0.02Pro169Glu-0.3 0.4 0.03C
12-C
16Sodium alkyl sulfate 20.0 20.0 20.0 20.0C
12-C
14N-methyl glucose amide 5.0 5.0 5.0 5.00C
11-C
13Sodium alkyl benzene sulfonate 10.0 10.0 10.0 10.00 sodium carbonate 25.0 25.0 25.0 25.00 sodium pyrophosphate 7.0 7.0 7.0 7.00 sodium phosphate trimer 7.0 7.0 7.0 7.00 zeolite A (0.1-10 μ) 5.0 5.0 5.0 5.00 carboxymethyl cellulose 0.2 0.2 0.2 0.20 polyacrylate (MW1400) 0.2 0.2 0.2 0.20 coconut alkyl MEA 5.0 5.0 5.0 5.00 brightening agents, spices 0.2 0.2 0.2 0.20 calcium sulfate 1.0 1.0 1.0 1.00 magnesium sulfate 1.0 1.0 1.0 1.00 water 4.0 4.0 4.0 4.00 fillers*Balance to 100%
*Can be selected from conventional material, for example lime carbonate, talcum, clay, silicate or the like.
In embodiment 67, replace Ser109Glu with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
In embodiment 68, replace Pro169Glu with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
In embodiment 69-70, any combination replacement Ser109Glu and Pro169Glu with hot enzyme variant body listed among the table 2-36 obtain substantially similar result.B. other cleaning composition
Except above-mentioned hard surface detergent, dishwashing detergent and fabric cleaning composition, one or more enzyme variant bodies of the present invention can add various the needs in other cleaning composition that insoluble hydrolysate separates substrate.Other cleaning composition comprises, but is not restricted to oral cavity cleaning composition, artificial tooth cleaning composition and contact lens cleaning composition.
1. oral cavity cleaning composition
In another embodiment of the present invention, the enzyme variant body of the present invention that comprises one or more pharmaceutically acceptable amounts in composition is to remove the deproteinize dirt from tooth or artificial tooth." oral cavity cleaning composition " used herein refers to the powder that cleans the teeth, toothpaste, tooth gel, tooth powder, mouth wash shua, oral spray, buccal cavity gel, chewing gum, lozenge, sachet, tablet, xanthan gel, prophylaxis pastes, artificial tooth treatment soln or the like.By the weight of composition, it is about 20% that cleaning composition preferably contains the 0.0001-that has an appointment, and more preferably from about 0.001%-is about 10%, one or more enzyme variant body of the present invention and pharmaceutically useful carriers of also preferred about 0.01%-about 5%.Medicine, medicament or inert fraction that " pharmaceutically useful " used herein refers to this term description are suitable for contacting with the tissue of human body and rudimentary animal, and do not have unfavorable toxicity, discomfort, unstable, pungency, anaphylaxis or the like, suitable with beneficial effect/risk-ratio.
It is about 99.99% that the pharmaceutically useful oral cavity wash vehicle component of oral cavity cleaning composition accounts for about 50%-usually by composition weight meter, and preferably about 65%-is about 99.99%, and more preferably from about 65%-about 99%.
Can be included in the cleaning composition of oral cavity of the present invention pharmaceutically useful carrier component and optionally component be well known by persons skilled in the art.Be used for various types of compositions, carrier component and the optional ingredient of oral cavity cleaning composition US5096700 at the Seibel of mandate on March 17th, 1992; Among Benedict, Bush that the US5028414 of the Sampathkumar that on July 2nd, 1991 authorized and on July 2nd, 1991 authorize and the US5028415 of Sunberg, classify this paper reference as.
The embodiment of oral cavity of the present invention cleaning composition illustrates in following embodiment.
Embodiment 71-74
The tooth-cleaning powder composition
Embodiment component 71 72 73 74Tyr218Ala, 2.000 3.500 1.500 2.000 Sorbitol Powders (70% aqueous solution) 35.000 35.000 35.000 35.000PEG-6
*1.000 1.000 1.000 1.000 silicon oxide tooth abrasive materials
*20.000 20.000 20.000 20.000 sodium fluoride 0.243 0.243 0.243 0.243 titanium dioxide 0.500 0.500 0.500 0.500 saccharin sodium 0.286 0.286 0.286 0.286 sodium alkyl sulfate (27.9% aqueous solution) 4.000 4.000 4.000 4.000 spices 1.040 1.040 1.040 1.040 carboxy vinyl polymers* *0.300 0.300 0.300 0.300Carrageenan
* * *0.800 0.800 0.800 0.800 water balance to 100%
*The polyoxyethylene glycol of PEG-6=molecular weight 600.
*The sedimentary silicon oxide Zeodent119 that provides by J.M.Huber
* *The Carbopol that provides by B.F.Goodrich Chemical Company
* * *The lota Carrageenan that provides by Hercules Chemical Company.
In embodiment 71-74, replace Tyr218Ala with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
Embodiment 75-78
Mouthwash agent composition
Embodiment component 75 76 77 78Ala164His+Ser220Glu 3.00 7.50 1.00 5.00SDA40 alcohol 8.00 8.00 8.00 8.00 spices 0.08 0.08 0.08 0.08 emulsification profit 0.08 0.08 0.08 0.08 sodium fluoride 0.05 0.05 0.05 0.05 glycerine 10.00 10.00 10.00 10.00 sweetener 0.02 0.02 0.02 0.02 benzoic acid 0.05 0.05 0.05 0.05 NaOH 0.20 0.20 0.20 0.20 dyestuff 0.04 0.04 0.04 0.04 water balances to 100% are in embodiment 75-78; Replace Ala164His+Ser220Glu with hot enzyme variant listed in table 2-36, obtain substantially similar result.
Embodiment 79-82
Lozenge composition
Embodiment component 79 80 81 82Leu221Val+Thr224Gln 0.01 0.03 0.10 0.02 D-sorbite 17.50 17.50 17.50 17.50 mannitol 17.50 17.50 17.50 17.50 starch 13.60 13.60 13.60 13.60 sweetener 1.20 1.20 1.20 1.20 spices 11.70 11.70 11.70 11.70 pigment 0.10 0.10 0.10 0.10 corn syrup balances to 100%
In embodiment 79-82, replace Leu221Val+Thr224Gln with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
Embodiment 83-86
The Chewing gum composition
Embodiment component 83 84 85 86Ser191Asp+Phe193Ile+Thr195Gly 0.03 0.02 0.10 0.05 Sorbitol Powder crystallization 38.44 38.40 38.40 38.40Palija-T gum
*20.00 20.00 20.00 20.00 Sorbitol Powders (70% aqueous solution), 22.00 22.00 22.00 22.00 mannitols, 10.00 10.00 10.00 10.00 glycerine, 7.56 7.56 7.56 7.56 spices 1.00 1.00 1.00 1.00
*L.A.Dreyfus Company provides.
In embodiment 83-86, replace Ser191Asp+Phe193Ile+Thr195Gly with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
2. the artificial tooth cleaning composition is in another embodiment of the present invention, and the artificial tooth cleaning composition that is used for washing artificial tooth outside the oral cavity contains one or more enzyme variant bodies of the present invention.This artificial tooth cleaning composition contains one or more enzyme variant bodies of significant quantity, preferably press composition weight meter, about 0.0001-is about 50%, and more preferably from about 0.001%-about 35%, one or more of also preferably about 0.01%-about 20% enzyme variant body of the present invention and artificial tooth wash vehicle.Various artificial tooth cleaning composition prescriptions are (referring to the US5055305 of for example Young, classifying this paper reference as) well known in the prior art as effervescent tablet or the like, are generally suitable for adding one or more enzyme variant bodies so that remove the deproteinize dirt from artificial tooth.
The embodiment of artificial tooth cleaning composition of the present invention is by following embodiment explanation.
Embodiment 87-90
Double-deck effervesce artificial tooth washing sheet
Acid layer Gly135Gln+Gly139Asn+ 1.0 1.5 0.01 0.05Asn140Gln+Ser141Asp tartaric acid 24.0 24.0 24.00 24.00 sodium carbonate 4.0 4.0 4.00 4.00 sulfamic acid 10.0 10.0 10.00 10.00PEG20000 4.0 4.0 4.00 4.00 sodium acid carbonate 24.5 24.5 24.50 24.50 potassium peroxydisulfate 15.0 15.0 15.00 15.00 acidic sodium pyrophosphate 7.0 7.0 7.00 7.00 pyrolysis silica 2.0 2.0 2.00 2.00TAED of embodiment component 87 88 89 90*7.0 7.0 7.00 7.00 castor-oil plant acyl group sulfosuccinate 0.5 0.5 0.50 0.50 spices 1.0 1.0 1.00 1.00 alkaline layer sodium perborate list hydrate 32.0 32.0 32.00 32.00 sodium acid carbonate 19.0 19.0 19.00 19.00EDTA 3.0 3.0 3.00 3.00 sodium phosphate trimer 12.0 12.0 12.00 12.00PEG20000 2.0 2.0 2.00 2.0 potassium peroxydisulfate 26.0 26.0 26.00 26.00 sodium carbonate 2.0 2.0 2.00 2.00 pyrolysis silica 2.0 2.0 2.00 2.00 dyestuffs/spices 2.0 2.0 2.00 2.00*Tetra acetyl ethylene diamine
In embodiment 87-90, replace Gly135Gln+Gly139Asn+Asn140Gln+Ser141Asp with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
2. contact lens cleaning composition
In another embodiment of the present invention, the contact lens cleaning composition contains one or more enzyme variant bodies of the present invention.This contact lens cleaning composition contains one or more enzyme variant bodies of significant quantity, preferably press composition weight meter, about 0.01-is about 50%, and more preferably from about 0.01%-about 20%, one or more of also preferably about 1%-about 5% enzyme variant body of the present invention and contact lens wash vehicle.Various contact lens cleaning composition prescriptions, for example tablet, liquid or the like are known (referring to the Davies that for example authorized on September 5th, 1989, Meaken and Rees, US4863627 in the prior art; The Huth that on May 24th, 1988 authorized once more, Lam and Kirai, USRe32672; The Schafer that authorized on September 2nd, 1986 is arranged, US4609493; Ogunbiyi and Smith that on September 1st, 1987 authorized, US4690793; The Ogunbiyi that on September 30th, 1986 authorized, Riedhammer and Smiht, US4614549; With the Ogata that authorized on August 25th, 1981, US4285738; All classify this paper reference as), be generally suitable for adding one or more enzyme variant bodies of the present invention so that remove the deproteinize dirt from contact lens.
The embodiment of contact lens cleaning composition of the present invention is by following embodiment explanation.
Embodiment 91-94
Enzymolysis contact lens washing soln
Embodiment component 91 92 93 94Leu221Gln 0.01 0.5 0.1 2.0 glucose 50.00 50.0 50.0 50.0 non-ionic surface active agents (polyoxyethylene-2.00 2.0 2.0 2.0 polyoxypropylene copolymers) anion surfactants (polyoxyethylene-1.00 1.0 1.0 1.0 alkyl phenyl ether sodium sulfovinates) sodium chloride 1.00 1.0 1.0 1.0 borax 0.30 0.3 0.3 0.3 water balances to 100%
In embodiment 91-94, replace Leu221Gln with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
Although described specific embodiments of the present invention, obviously those skilled in the art can make various changes and improvements of the present invention and can not run counter to the spirit and scope of the present invention.In the appended claims, scope of the present invention has covered all these improvement.
Claims (9)
1. the hot enzyme variant body that has the modified amino acid sequence of hot enzyme (thermitase) wild-type amino acid sequence, wild-type amino acid sequence comprise the first ring zone, the second ring zone, the 3rd ring zone, zone, Fourth Ring, zone, five rings and the 6th ring zone; Wherein contain substituting group on one or more sites of the aminoacid sequence of Xiu Shiing in one or more rings zone; Wherein
A. occur on site 66,69,70,72 or 73 one or more when replacing when occurring in the first ring zone, replacing; Wherein
A. when replacement occurred in site 66, substituted amino acid was Asn;
B. when replacement occurred in site 69, substituted amino acid was Gln;
C. when replacement occurred in site 70, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser;
D. when replacement occurred in site 72, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser;
E. when replacement occurred in site 73, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser;
B. occur on site 103,104,105,106,108,110,112,113 or 114 one or more when replacing when occurring in the second ring zone, replacing; Wherein
A. when replacement occurred in site 103, substituted amino acid was Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Met, Pro, Ser or Thr;
B. when replacement occurred in site 104, substituted amino acid was Ala, Asn, Asp, Cys, Gln, Gly, His, Ile, Met, Pro or Ser;
C. when replacement occurred in site 105, substituted amino acid was Glu;
D. when replacement occurred in site 106, substituted amino acid was Gln;
E. when replacement occurred in site 108, substituted amino acid was Asn, Gln, Pro or Ser;
F. when replacement occurred in site 110, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser;
G. when replacement occurred in site 112, substituted amino acid was Asn, Asp, Cys, Gln, Glu, His, Ile, Met, Phe, Pro, Thr or Tyr;
H. when replacement occurred in site 113, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser; With
I. when replacement occurred in site 114, substituted amino acid was Asn, Asp, Gln, Glu, Gly, His, Pro, Ser or Thr;
C. take place on site 134,135,136,137,138,139 or 141 one or more when replacing when occurring in the 3rd ring zone, replacing; Wherein
A. when replacement occurred in site 134, substituted amino acid was Ala, Asn, Cys, Gln, Gly, His, Met, Pro, Ser, Thr or Val;
B. when replacement occurred in site 135, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser;
C. when replacement occurred in site 136, substituted amino acid was Pro;
D. when replacement occurred in site 137, substituted amino acid was Asn, Asp, Gln, Glu or Ser;
E. when replacement occurred in site 138, substituted amino acid was Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Met, Pro, Ser or Thr;
F. when replacement occurred in site 139, substituted amino acid was Asn, Gln, Pro or Ser; With
G. when replacement occurred in site 141, substituted amino acid was Asp or Glu;
D. when replace when occurring in the zone, Fourth Ring, replace occur in site 167,169 or 171 one or more on; Wherein
A. when replacement occurred in site 167, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser;
When b occurred in site 169 when replacement, substituted amino acid was Asn, Asp, Gln, Glu, Gly or Ser; With
C. when replacement occurred in site 171, substituted amino acid was His, Ile, Leu, Met or Pro;
E. when replace when occurring in the zone, five rings, replace occur in site 193 one or more on; Wherein
A. when replacement occurred in site 193, substituted amino acid was Asn, Cys, Gln, His, Ile, Met, Thr or Tyr;
F. occur on site 204,205,206,207,208,209,210,211,212,213,214,215,216,217,220,221,223 or 224 one or more, wherein when replacing when occurring in the 6th ring zone, replacing
A. when replacement occurred in site 204, substituted amino acid was Asn, Asp, Gln, Glu, Gly, His, Pro, Ser or Thr;
B. when replacement occurred in site 205, substituted amino acid was Asn, Asp, Gln, Glu, Gly or Ser;
C. when replacement occurred in site 206, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser;
D. when replacement occurred in site 207, substituted amino acid was Asp or Glu;
E. when replacement occurred in site 208, substituted amino acid was Asp or Glu;
F. when replacement occurred in site 209, substituted amino acid was Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Leu, Met, Pro, Ser, Thr or Val;
G. when replacement occurred in site 210, substituted amino acid was Asp, His, Ile, Leu, Met or Pro;
H. when replacement occurred in site 211, substituted amino acid was Asp or Glu;
I. when replacement occurred in site 212, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser;
J. when replacement occurred in site 213, substituted amino acid was Asp, Glu, His, Ile, Leu, Met, Phe, Pro or Val;
I. when replacement occurred in site 214, substituted amino acid was Asn, Gln, Gly or Ser;
J. when replacement occurred in site 215, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser;
M. when replacement occurred in site 216, substituted amino acid was Asp or Glu;
N. when replacement occurred in site 217, substituted amino acid was Asp, Glu or Pro;
O. when replacement occurred in site 220, substituted amino acid was Asp or Glu;
P. when replacement occurred in site 221, substituted amino acid was Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Met, Pro, Ser, Thr or Val;
Q. when replacement occurred in site 222, substituted amino acid was Asp or Glu;
R. when replacement occurred in site 223, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser;
S. when replacement occurred in site 224, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser;
Thereby, to compare with the hot enzyme of wild-type, hot enzyme variant body has the hydrolytic action of the adsorption and the increase of reduction to not dissolving substrate.
2. the hot enzyme variant body of claim 1, wherein one or more substituting groups occur in the first ring zone.
3. the hot enzyme variant body of claim 1, wherein one or more substituting groups occur in the second ring zone.
4. the hot enzyme variant body of claim 1, wherein one or more substituting groups occur in the 3rd ring zone.
5. the hot enzyme variant body of claim 1, wherein one or more substituting groups occur in the zone, Fourth Ring.
6. the hot enzyme variant body of claim 1, wherein one or more substituting groups occur in the zone, five rings.
7. the hot enzyme variant body of claim 1, wherein one or more substituting groups occur in the 6th ring zone.
8. cleaning composition that is selected from hard surface detergent compositions, dish washing compositions, oral cavity cleaning composition, artificial tooth cleaning composition, contact lens cleaning composition and fabric cleaning composition is characterized in that cleaning composition wherein contains any one hot enzyme variant body and the cleaning composition carrier of claim 1-7; Cleaning composition preferably hard surface detergent compositions or cleaning composition is a fabric cleaning composition; Composition preferably contains by composition weight meter at least about 5% tensio-active agent with at least about 5% auxiliary agent; Composition also preferably contains the cleaning composition material that is selected from solvent, buffer reagent, enzyme, dirt release agent, clay stain remover, dispersion agent, whitening agent, froth suppressor, fabric softener, suds booster, enzyme stabilizers, SYNTHETIC OPTICAL WHITNER, dyestuff, spices and their mixture.
9. the dna sequence dna of the hot enzyme variant body of any one of coding claim 1-7.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US40157395A | 1995-03-09 | 1995-03-09 | |
US08/401,573 | 1995-03-09 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1183118A true CN1183118A (en) | 1998-05-27 |
Family
ID=23588283
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN96193608A Pending CN1183118A (en) | 1995-03-09 | 1996-03-06 | Thermitase variants having decreased adsorption and increased hydrolysis |
Country Status (14)
Country | Link |
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EP (1) | EP0815244A1 (en) |
JP (1) | JPH11501816A (en) |
CN (1) | CN1183118A (en) |
AU (1) | AU5182996A (en) |
BR (1) | BR9607756A (en) |
CA (1) | CA2214578A1 (en) |
CZ (1) | CZ280097A3 (en) |
HU (1) | HUP9802069A3 (en) |
IL (1) | IL117352A0 (en) |
IN (1) | IN187236B (en) |
MA (1) | MA23819A1 (en) |
MX (1) | MX9706846A (en) |
WO (1) | WO1996028558A1 (en) |
ZA (1) | ZA961822B (en) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU1200997A (en) * | 1995-12-22 | 1997-07-17 | Helix Biotechnology Ltd | Thermostable proteolytic enzyme from thermoactinomyces thalpophilus thm1 |
CN1136311C (en) * | 1996-11-04 | 2004-01-28 | 诺沃奇梅兹有限公司 | Subtilase variants and compositions |
JPH10204500A (en) * | 1997-01-20 | 1998-08-04 | Soft Kyukyu Corp:Kk | Effervescent tablet detergent |
AR015977A1 (en) * | 1997-10-23 | 2001-05-30 | Genencor Int | PROTEASA VARIANTS MULTIPLY SUBSTITUTED WITH ALTERED NET LOAD FOR USE IN DETERGENTS |
ES2367505T3 (en) | 1997-10-23 | 2011-11-04 | Danisco Us Inc. | PROTEASE VARIANTS WITH MULTIPLE SUBSTITUTIONS WITH ALTERED NET LOAD FOR USE IN DETERGENTS. |
ES2281976T3 (en) * | 1998-12-18 | 2007-10-01 | Novozymes A/S | SUBTILLABLE ENZYMES OF SUB-GROUPS I-S1 AND I-S2 THAT HAVE AN ADDITIONAL AMINO ACID RESIDUE IN THE LOOP REGION OF THE ACTIVE SITE. |
KR100660746B1 (en) * | 1998-12-18 | 2006-12-22 | 노보자임스 에이/에스 | Subtilase enzymes of the i-s1 and i-s2 sub-groups having an additional amino acid residue in an active site loop region |
US7319112B2 (en) | 2000-07-14 | 2008-01-15 | The Procter & Gamble Co. | Non-halogenated antibacterial agents and processes for making same |
JP5339672B2 (en) * | 2006-07-03 | 2013-11-13 | 小林製薬株式会社 | Bleach cleaning composition |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5116741A (en) * | 1988-04-12 | 1992-05-26 | Genex Corporation | Biosynthetic uses of thermostable proteases |
DE69034159T2 (en) * | 1989-06-26 | 2005-02-17 | Unilever N.V. | Enzymatic detergent compositions |
JPH04500384A (en) * | 1989-06-26 | 1992-01-23 | ユニリーバー・ナームローゼ・ベンノートシヤープ | Enzyme detergent composition |
DK316989D0 (en) * | 1989-06-26 | 1989-06-26 | Novo Nordisk As | ENZYMES |
ES2275265T3 (en) * | 1993-09-15 | 2007-06-01 | THE PROCTER & GAMBLE COMPANY | BPN SUBTILISIN VARIANTS WITH REDUCED ADSORTION AND IMPROVED HYDROLYSIS. |
-
1996
- 1996-03-04 IL IL11735296A patent/IL117352A0/en unknown
- 1996-03-06 MX MX9706846A patent/MX9706846A/en unknown
- 1996-03-06 BR BR9607756A patent/BR9607756A/en not_active Application Discontinuation
- 1996-03-06 CZ CZ972800A patent/CZ280097A3/en unknown
- 1996-03-06 ZA ZA961822A patent/ZA961822B/en unknown
- 1996-03-06 AU AU51829/96A patent/AU5182996A/en not_active Abandoned
- 1996-03-06 EP EP96908663A patent/EP0815244A1/en not_active Withdrawn
- 1996-03-06 JP JP8527693A patent/JPH11501816A/en active Pending
- 1996-03-06 HU HU9802069A patent/HUP9802069A3/en unknown
- 1996-03-06 IN IN457DE1996 patent/IN187236B/en unknown
- 1996-03-06 CN CN96193608A patent/CN1183118A/en active Pending
- 1996-03-06 CA CA002214578A patent/CA2214578A1/en not_active Abandoned
- 1996-03-06 WO PCT/US1996/003009 patent/WO1996028558A1/en not_active Application Discontinuation
- 1996-03-07 MA MA24176A patent/MA23819A1/en unknown
Also Published As
Publication number | Publication date |
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CZ280097A3 (en) | 1998-01-14 |
BR9607756A (en) | 1999-03-30 |
MX9706846A (en) | 1997-11-29 |
HUP9802069A3 (en) | 2000-11-28 |
EP0815244A1 (en) | 1998-01-07 |
MA23819A1 (en) | 1996-10-01 |
ZA961822B (en) | 1996-09-11 |
HUP9802069A2 (en) | 1998-12-28 |
CA2214578A1 (en) | 1996-09-19 |
IN187236B (en) | 2002-03-09 |
WO1996028558A1 (en) | 1996-09-19 |
JPH11501816A (en) | 1999-02-16 |
AU5182996A (en) | 1996-10-02 |
IL117352A0 (en) | 1996-07-23 |
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