| Elimination of P1 arginine 393 interaction with underlying glutamic acid 255 partially activates antithrombin III for thrombin inhibition but not factor Xa inhibition. | |
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MedLine Citation:
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PMID: 11971909 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The mechanism for heparin activation of antithrombin III has been postulated to involve disruption of interactions between its reactive loop P1 residue and Glu(255) on the underlying protein surface. To test this hypothesis, the potential P1-constraining Arg(393)-Glu(255) hydrogen bond and ionic interactions were eliminated by converting Glu(255) to alanine. E255A and wild-type ATIIIs have identical reactive loop sequences (including the P1 and P14 residues), but differ in that Glu(255)-mediated, P1-constraining interactions with the underlying surface cannot form in the mutant. Relative to its wild-type parent, E255A had a 5-fold higher affinity for heparin and pentasaccharide. In the absence of cofactor, E255A exhibited a 5-fold activation of thrombin inhibition but no activation of factor Xa inhibition. Pentasaccharide addition elicited no further activation of thrombin inhibition but increased the factor Xa inhibition rate 100-fold. E255A heparin-dependent thrombin and factor Xa inhibition rates were 1000- and 2-fold faster, respectively, than pentasaccharide-catalyzed rates. Although "approximation" is the predominant factor in heparin activation of ATIII thrombin inhibition, and removal of the P1 constraint plays a distinct but minor role, the primary determinant for activation of factor Xa inhibition is the pentasaccharide-induced conformational change, with approximation making a further minor contribution, and removal of the P1 constraint playing no role at all. |
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Authors:
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Mohamad Aman Jairajpuri; Aiqin Lu; Susan C Bock |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. Date: 2002-04-23 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 277 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2002 Jul |
Date Detail:
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Created Date: 2002-07-01 Completed Date: 2002-08-27 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 24460-5 Citation Subset: IM |
Affiliation:
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Department of Medicine, University of Utah, Salt Lake City, Utah 84132, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Sequence Amino Acid Substitution Animals Antithrombin III / chemistry, metabolism* Arginine* Base Sequence Binding Sites Cell Line Factor Xa / metabolism* Glutamic Acid* Heparin / pharmacology Humans Models, Molecular Mutagenesis, Site-Directed Polymerase Chain Reaction Protein Conformation Recombinant Proteins / chemistry, metabolism Spodoptera Thrombin / antagonists & inhibitors* Transfection |
| Grant Support | |
ID/Acronym/Agency:
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R01-HL30712/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Recombinant Proteins; 56-86-0/Glutamic Acid; 74-79-3/Arginine; 9000-94-6/Antithrombin III; 9005-49-6/Heparin; EC 3.4.21.5/Thrombin; EC 3.4.21.6/Factor Xa |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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