Document Detail

Crystallographic analysis of potent and selective factor Xa inhibitors complexed to bovine trypsin.
MedLine Citation:
PMID:  10417407     Owner:  NLM     Status:  MEDLINE    
Factor Xa is a serine protease which activates thrombin (factor IIa) and plays a key regulatory role in the blood-coagulation cascade. Factor Xa is, therefore, an important target for the design of anti-thrombotics. Both factor Xa and thrombin share sequence and structural homology with trypsin. As part of a factor Xa inhibitor-design program, a number of factor Xa inhibitors were crystallographically studied complexed to bovine trypsin. The structures of one diaryl benzimidazole, one diaryl carbazole and three diaryloxypyridines are described. All five compounds bind to trypsin in an extended conformation, with an amidinoaryl group in the S1 pocket and a second basic/hydrophobic moiety bound in the S4 pocket. These binding modes all bear a resemblance to the reported binding mode of DX-9065a in bovine trypsin and human factor Xa.
M Whitlow; D O Arnaiz; B O Buckman; D D Davey; B Griedel; W J Guilford; S K Koovakkat; A Liang; R Mohan; G B Phillips; M Seto; K J Shaw; W Xu; Z Zhao; D R Light; M M Morrissey
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Publication Detail:
Type:  In Vitro; Journal Article    
Journal Detail:
Title:  Acta crystallographica. Section D, Biological crystallography     Volume:  55     ISSN:  0907-4449     ISO Abbreviation:  Acta Crystallogr. D Biol. Crystallogr.     Publication Date:  1999 Aug 
Date Detail:
Created Date:  1999-09-23     Completed Date:  1999-09-23     Revised Date:  2007-07-24    
Medline Journal Info:
Nlm Unique ID:  9305878     Medline TA:  Acta Crystallogr D Biol Crystallogr     Country:  DENMARK    
Other Details:
Languages:  eng     Pagination:  1395-404     Citation Subset:  IM    
Berlex Biosciences, 15049 San Pablo Avenue, PO Box 4099, Richmond, California 94804, USA.
Data Bank Information
Bank Name/Acc. No.:
PDB/1QA0;  1QB1;  1QB6;  1QB9;  1QBN;  1QBO
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MeSH Terms
Crystallography, X-Ray
Drug Design
Factor Xa / antagonists & inhibitors*
Macromolecular Substances
Models, Molecular
Molecular Conformation
Protein Binding
Protein Conformation
Trypsin / chemistry*
Reg. No./Substance:
0/Macromolecular Substances; EC; EC Xa

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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