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Activation of antithrombin as a factor IXa and Xa inhibitor involves mitigation of repression rather than positive enhancement
Author(s) -
Gettins Peter G.W.,
Olson Steven T.
Publication year - 2009
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2009.10.005
Subject(s) - antithrombin , allosteric regulation , chemistry , factor ixa , heparin , mechanism (biology) , antithrombins , arginine , thrombin , biochemistry , biophysics , microbiology and biotechnology , enzyme , factor x , biology , amino acid , immunology , physics , platelet , quantum mechanics
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.