Conformational conversion of antithrombin to a fully activated substrate of factor Xa without need for heparin.

Abstract

Regulation of the inhibitory activity of antithrombin, the principal inhibitor of the blood-clotting proteinases factor Xa and thrombin, is accomplished by binding to heparin. We report here an antithrombin variant in which serine at position 380, 14 residues N-terminal from the reactive bond and at a hinge point in the structure, was replaced by cysteine to test a proposed mechanism of heparin activation of antithrombin as an inhibitor of factor Xa. By derivatization of this cysteine with a bulky group, fluorescein, the antithrombin became permanently and fully activated toward reaction with factor Xa in a manner analogous to heparin activation, albeit as a substrate. These findings establish a structural basis for the mechanism of heparin activation of antithrombin against factor Xa in agreement with that proposed from an X-ray structure of antithrombin.

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@article{Huntington1998ConformationalCO, title={Conformational conversion of antithrombin to a fully activated substrate of factor Xa without need for heparin.}, author={James A. Huntington and Peter G W Gettins}, journal={Biochemistry}, year={1998}, volume={37 10}, pages={3272-7} }