IMPLICATIONS FOR FUNCTION AND THERAPY OF A 2.9 ANGSTROM STRUCTURE OF BINARY-COMPLEXED ANTITHROMBIN

The crystal structure of a binary complex of human antithrombin with a peptide of the same sequence as its reactive loop (P-14-P-3) has been determined at 2.9 Angstrom. The peptide binds as the middle strand s4 A in the A P-sheet, homologously to that of the reactive loop in the l atent and cleaved forms of antithrombin. Peptide binding results in th e complete expulsion of the hinge region of the loop from the A beta-s heet although the conformation differs from that of heparin-activated antithrombin. The 36-fold increase in the rate of reaction of the bina ry complex with factor Xa indicates that full loop expulsion alone is not sufficient for complete heparin activation of antithrombin but tha t this is also dependent on the overall conformation of the molecule. Previous studies have demonstrated that reactive loop peptides can blo ck or reverse the polymerisation of serpins associated with cirrhosis and thrombosis. The antithrombin binary complex structure defines the precise localisation of the blocking peptide in a serpin and provides the basis for rational drug design for mimetics that will prevent poly merisation in vivo and so ameliorate the associated disease. (C) 1998 Academic Press.