STRUCTURAL BASIS FOR SERPIN INHIBITOR ACTIVITY

The mechanism of formation and the structures of serpin-inhibitor comp lexes are not completely understood, despite detailed knowledge of the structures of a number of cleaved and uncleaved inhibitor, noninhibit or, and latent serpins, It has been proposed from comparison of inhibi tor and noninhibitor serpins in the cleaved and uncleaved forms that i nsertion of strand s4A into preexisting beta-sheet A is a requirement for serpin inhibitor activity. We have investigated the role of this s trand in formation of serpin-proteinase complexes and in serpin inhibi tor activity through homology modeling of wild type inhibitor, mutant substrate, and latent serpins, and of putative serpin-proteinase compl exes. These models explain the high stability of the complexes and pro vide an understanding of substrate behavior in serpins with point muta tions in s4A and of latency in plasmingoen activator inhibitor I. (C) 1995 Wiley-Liss, Inc.