The anticoagulant activation of antithrombin by heparin

摘要

Antithrombin, a plasma serpin, is relatively inactive as an inhibitor of the coagulation proteases until it binds to the heparan side chains that line the microvascula- ture. The binding specifically occurs to a core pentasaccharide present both in the heparans and in their therapeutic deriv- ative heparin. The accompanying conformational change of antithrombin is revealed in a 2.9-A deg structure of a dimer of latent and active antithrombins, each in complex with the high-affinity pentasaccharide. Inhibitory activation results from a shift in the main sheet of the molecule from a partially six-stranded to a five-stranded form, with extrusion of the reactive center loop to give a more exposed orientation.