FROM PEPTIDE TO NONPEPTIDE .1. THE ELUCIDATION OF A BIOACTIVE CONFORMATION OF THE ARGININE-GLYCINE-ASPARTIC ACID RECOGNITION SEQUENCE

被引:60
作者
MCDOWELL, RS [1 ]
GADEK, TR [1 ]
BARKER, PL [1 ]
BURDICK, DJ [1 ]
CHAN, KS [1 ]
QUAN, CL [1 ]
SKELTON, N [1 ]
STRUBLE, M [1 ]
THORSETT, ED [1 ]
TISCHLER, M [1 ]
TOM, JYK [1 ]
WEBB, TR [1 ]
BURNIER, JP [1 ]
机构
[1] GENENTECH INC,DEPT PROT ENGN,S SAN FRANCISCO,CA 94080
关键词
D O I
10.1021/ja00091a007
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
An ensemble molecular dynamics method is used to map consensus conformations of the arginine-glycine-aspartic acid (RGD) sequence which are accessible to a set of potent, structurally diverse inhibitors of fibrinogen-glycoprotein IIbIIIa association. This procedure identifies a dominant low-energy RGD conformation that is consistent with the previously determined solution structure of a highly potent RGD-containing peptide. Enforcing an alternate, higher energy conformation is shown to eliminate activity. These observations strongly suggest that the consensus conformation identified is responsible for inhibiting fibrinogen-glycoprotein IIbIIIa binding, thus providing a structural rationale for the de novo design of potent non-peptidal inhibitors of platelet aggregation.
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页码:5069 / 5076
页数:8
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