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Activation of antithrombin as a factor IXa and Xa inhibitor involves mitigation of repression rather than positive enhancement.

ABSTRACT: Allosteric activation of antithrombin as a rapid inhibitor of factors IXa and Xa requires binding of a high-affinity heparin pentasaccharide. The currently-accepted mechanism involves removal of a constraint on the antithrombin reactive center loop (RCL) so that the proteinase can simultaneously engage both the P1 arginine and an exosite at Y253. Recent results suggest that this mechanism is incorrect in that activation can be achieved without loop expulsion, while the exosite can be engaged in both low and high activity states. We propose a quite different mechanism in which heparin activates antithrombin by mitigating an unfavorable surface interaction, by altering its nature, and by moving the attached proteinase away from the site of the unfavorable interaction through RCL expulsion.

SUBMITTER: Gettins PG

PROVIDER: S-EPMC3821923 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Activation of antithrombin as a factor IXa and Xa inhibitor involves mitigation of repression rather than positive enhancement.

Gettins Peter G W PG Olson Steven T ST

FEBS letters 20091009 21

Allosteric activation of antithrombin as a rapid inhibitor of factors IXa and Xa requires binding of a high-affinity heparin pentasaccharide. The currently-accepted mechanism involves removal of a constraint on the antithrombin reactive center loop (RCL) so that the proteinase can simultaneously engage both the P1 arginine and an exosite at Y253. Recent results suggest that this mechanism is incorrect in that activation can be achieved without loop expulsion, while the exosite can be engaged in ...[more]

PMID: 19818773

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The allosteric mechanism of activation of antithrombin as an inhibitor of factor IXa and factor Xa: heparin-independent full activation through mutations adjacent to helix D.

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| S-EPMC10568284 | biostudies-literature

Designing nonsaccharide, allosteric activators of antithrombin for accelerated inhibition of factor Xa.

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Structure-function of anticoagulant TIX-5, the inhibitor of factor Xa-mediated FV activation.

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| S-EPMC8360041 | biostudies-literature

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