Document Detail


Transmission of conformational change from the heparin binding site to the reactive center of antithrombin.
MedLine Citation:
PMID:  8357789     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Heparin greatly increases the rates at which antithrombin inhibits target proteinases. An important part of this rate acceleration is a heparin-induced conformational change in antithrombin. To answer the question of whether or not this change is transmitted to the reactive center, we have prepared a recombinant P1 mutant of antithrombin, R393C, labeled the cysteine with nitrobenzofuran (NBD) fluorophore, and examined the perturbation of NBD fluorescence intensity as a function of bound sulfated oligosaccharide. Two high-affinity heparins, low-affinity heparin, and dextran sulfate were used. We found (i) that binding to antithrombin of all these oligosaccharides resulted in transmission of conformational change to P1 in the reactive center, (ii) that these oligosaccharides all gave enhancements of the rate of inhibition of factor Xa beyond any contribution from surface approximation, and (iii) that the degree of perturbation of P1 correlated with the enhancement of the rate of factor Xa inhibition that was not due to surface approximation.
Authors:
P G Gettins; B Fan; B C Crews; I V Turko; S T Olson; V J Streusand
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Biochemistry     Volume:  32     ISSN:  0006-2960     ISO Abbreviation:  Biochemistry     Publication Date:  1993 Aug 
Date Detail:
Created Date:  1993-09-27     Completed Date:  1993-09-27     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0370623     Medline TA:  Biochemistry     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  8385-9     Citation Subset:  IM    
Affiliation:
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
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MeSH Terms
Descriptor/Qualifier:
Antithrombins / chemistry*,  genetics,  metabolism*
Base Sequence
Binding Sites
Dextran Sulfate / metabolism,  pharmacology
Heparin / metabolism,  pharmacology*
Humans
Kinetics
Molecular Sequence Data
Mutagenesis, Site-Directed
Oligonucleotides, Antisense
Protein Conformation*
Recombinant Proteins / chemistry,  metabolism
Grant Support
ID/Acronym/Agency:
ES00267/ES/NIEHS NIH HHS; HL39888/HL/NHLBI NIH HHS; HL49234/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Antithrombins; 0/Oligonucleotides, Antisense; 0/Recombinant Proteins; 9005-49-6/Heparin; 9042-14-2/Dextran Sulfate

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


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