Conformational changes in serpins: II. The mechanism of activation of antithrombin by heparin

Antithrombin, uniquely among plasma serpins acting as proteinase inhibitors in the control of the blood coagulation cascade, circulates in a relativel y inactive form. Its activation by heparin, and specifically by a pentasacc haride core of heparin, has been shown to involve release of the peptide lo op containing the reactive centre from partial insertion in the A sheet of the molecule. Here we compare the structures of the circulating inactive fo rm of antithrombin with the activated structure in complex with heparin pen tasaccharide. We show that the rearrangement of the reactive centre loop th at occurs upon activation is part of a widespread conformational change inv olving a realignment of the two major domains of the molecule. We also exam ine natural mutants that possess high affinity for heparin pentasaccharide, and relate the kinetics of their interaction with heparin pentasaccharide to the structural transitions occuring in the activation process. (C) 2000 Academic Press.