MODELING OF SERPIN-PROTEASE COMPLEXES - ANTITHROMBIN-THROMBIN, ALPHA(1)-ANTITRYPSIN (358MET-]ARG)-THROMBIN, ALPHA(1)-ANTITRYPSIN (358MET-]ARG)-TRYPSIN, AND ANTITRYPSIN-ELASTASE

Based on the most recent available crystal structures and biochemical studies of protease complexes of normal and mutant serine protease inh ibitors (serpins), we have built models of the complexes: alpha(1)-ant itrypsin + human neutrophil elastase; alpha(1)-antitrypsin Pittsburgh (358Met-->Arg) (Scott et al., J. Clin. Invest. 77:631-634, 1986) + try psin; alpha(1)-antitrypsin Pittsburgh (358Met-->Arg) + thrombin; and a ntithrombin + thrombin, All serpin sequences correspond to human molec ules, The models show correct stereochemistry and no steric clashes be tween protease and inhibitor. The main structural differences in the s erpins from the parent structures are: (If the react;ive center loop i s inserted into the A-sheet as far as P12; (2) strand s1C is removed f rom the C-sheet; and (3) the C-terminus has changed conformation and i nteracts with the protease, In the absence of an X-ray structure deter mination of a serpin-protease complex, the demonstration that insertio n of the reactive center loop into the A-sheet as far as P12 is stereo chemically feasible provides structures of a protease-bound conformati on of intact serpins with which to rationalize the properties of mutan ts, guide the design of experiments, and form a basis for further mode ling studies, such as the investigation of the interaction of heparin with serpin-protease complexes. (C) 1996 Wiley-Liss, Inc.