Document Detail


Molecular basis of factor IXa recognition by heparin-activated antithrombin revealed by a 1.7-A structure of the ternary complex.
MedLine Citation:
PMID:  20080729     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Factor (f) IXa is a critical enzyme for the formation of stable blood clots, and its deficiency results in hemophilia. The enzyme functions at the confluence of the intrinsic and extrinsic pathways by binding to fVIIIa and rapidly generating fXa. In spite of its importance, little is known about how fIXa recognizes its cofactor, its substrate, or its only known inhibitor, antithrombin (AT). However, it is clear that fIXa requires extensive exosite interactions to present substrates for efficient cleavage. Here we describe the 1.7-A crystal structure of fIXa in its recognition (Michaelis) complex with heparin-activated AT. It represents the highest resolution structure of both proteins and allows us to address several outstanding issues. The structure reveals why the heparin-induced conformational change in AT is required to permit simultaneous active-site and exosite interactions with fIXa and the nature of these interactions. The reactive center loop of AT has evolved to specifically inhibit fIXa, with a P2 Gly so as not to clash with Tyr99 on fIXa, a P4 Ile to fit snugly into the S4 pocket, and a C-terminal extension to exploit a unique wall-like feature of the active-site cleft. Arg150 is at the center of the exosite interface, interacting with AT residues on beta-sheet C. A surprising crystal contact is observed between the heparin pentasaccharide and fIXa, revealing a plausible mode of binding that would allow longer heparin chains to bridge the complex.
Authors:
Daniel J D Johnson; Jonathan Langdown; James A Huntington
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-12-22
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  107     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2010 Jan 
Date Detail:
Created Date:  2010-01-18     Completed Date:  2010-02-26     Revised Date:  2014-02-19    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  645-50     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Antithrombins / chemistry*,  metabolism*
Binding Sites
Blood Coagulation / physiology
Catalytic Domain
Crystallography, X-Ray
Factor IXa / chemistry*,  metabolism*
Heparin / chemistry,  pharmacology*
Humans
Models, Molecular
Protein Binding
Protein Conformation
Swine
Grant Support
ID/Acronym/Agency:
G0601596//Medical Research Council; G117/444//Medical Research Council; //British Heart Foundation; //Medical Research Council
Chemical
Reg. No./Substance:
0/Antithrombins; 9005-49-6/Heparin; EC 3.4.21.22/Factor IXa
Comments/Corrections

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


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