Rationally designed polysaccharide lyases derived from heparinase I
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-038/51
C12N-009/88
C07H-021/04
출원번호
US-0066481
(1999-01-19)
국제출원번호
PCT/US96/17310
(1996-10-30)
§371/§102 date
19990119
(19990119)
국제공개번호
WO-9716556
(1997-05-09)
발명자
/ 주소
Godavarti Ranganathan
Sasisekharan Ram
Ernst Steffen,DKX
Venkataraman Ganesh
Cooney Charles L.
Langer Robert
출원인 / 주소
Massachusetts Institute of Technology
대리인 / 주소
Wolf, Greenfield & Sacks, P.C.
인용정보
피인용 횟수 :
50인용 특허 :
41
초록
Modified heparinases having altered binding specificity and activity are provided. Isolated nucleic acids encoding the same as as vectors and host cells are provided. Methods for using the modified heparinases are also provided.
대표청구항▼
[ We claim:] [1.]1. An enzymatically active substantially pure polysaccharide lyase comprising the amino acid sequence of the mature peptide of SEQ ID NO: 2 wherein at least one amino acid residue has been substituted and whereinthe substitution is selected from the group consisting of (a) a substit
[ We claim:] [1.]1. An enzymatically active substantially pure polysaccharide lyase comprising the amino acid sequence of the mature peptide of SEQ ID NO: 2 wherein at least one amino acid residue has been substituted and whereinthe substitution is selected from the group consisting of (a) a substitution of a cysteine residue corresponding to position 135 of SEQ ID NO: 2 with a residue selected from the group consisting of aspartate, glutamate, serine, threonine, and histidine; (b) a conservative substitution of a residue of a Cardin-Weintraub-like heparin-binding sequence XBBXXXBXB (SEQ ID NO:3) corresponding to positions 197-205 or 208-212 of SEQ ID NO: 2, wherein the conservative substitution includes the replacement of a basic residue, B, with a basic amino acid or replacement of a non-basic residue, X, with an amino acid which is a conservative substitution; (c) a conservative substitution of a residue of an EF-hand-like calcium binding sequence of SEQ ID NO: 9 corresponding to positions 206-220 of SEQ ID NO: 2; (d) a conservative substitution of a residue of a turn of a PB1, PB2 or PB3 .beta.-sheet domain of SEQ ID NO: 2, the turns of PB1 .beta.-sheet domain corresponding to positions 26-30, 48-51, 67-70, 107-110, 128-131, 154-156, 171-175, 215-218, 234-238, 261-264, 297-299, or 323-329 of SEQ ID NO: 2, the turns of PB2 .beta.-sheet domain corresponding to positions 35-38, 53-56, 75-77, 116-117, 140-143, 159-160, 178-179, 225-227, 265-267, or 301-304 of SEQ ID NO: 2, and the turns of PB3 .beta.-sheet domain corresponding to positions 120-122, 146-148, 164-167, 181-184, 243-247, or 338-341 of SEQ ID NO: 2; (e) a non-conservative substitution of a cysteine residue corresponding to position 297 of SEQ ID NO: 2; (f) a non-conservative substitution of a residue of a turn of a PB1, PB2 or PB3 .beta.-sheet domain of SEQ ID NO: 2 wherein the turns of PB1 .beta.-sheet domain corresponding to positions 26-30, 48-51, 67-70, 107-110, 128-131, 154-156, 171-175, 215-218, 261-264, 297-299, or 323-329 of SEQ ID NO: 2, the turns of PB2 .beta.-sheet domain corresponding to positions 35-38, 53-56, 75-77, 116-117, 140-143, 159-160, 178-179, 225-227, 265-267, or 301-304 of SEQ ID NO: 2, and the turns of PB3 .beta.-sheet domain corresponding to positions 120-122, 146-148, 164-167, 181-184, 243-247, or 338-341 of SEQ ID NO: 2; (g) a substitution of a histidine residue corresponding to position 203 of SEQ ID NO: 2 with a residue selected from the group consisting of aspartate, glutamate, serine, threonine and cysteine; (h) a substitution of a lysine residue corresponding to position 198, 199, 205, 208, 209, 211 or 214 of SEQ ID NO: 2 with a residue selected from the group consisting of non-polar amino acids, polar amino acids, and acidic amino acids; (i) a substitution of a polar or non-polar amino acid for a residue corresponding to a position of SEQ ID NO: 2 selected from the group consisting of Phe197, Asn200, Asp204, Glu207, Asp210, Asp212 and Gly213; and (j) a non-conservative substitution of a serine residue corresponding to position 39 of SEQ ID NO: 2.
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