ABSTRACT
The first x-ray structure determination of a serpin was of a reactive-site-modified form of the normal (M variant) human alpha 1-antitrypsin (alAT*), also called alpha 1-proteinase inhibitor (1). After cleavage at the reactive site Met358Ser359 by chymotrypsinogen A, alAT* formed crystals that diffracted to a resolution of 3.0A (2). The three-dimensional structure revealed that a major conformational rearrangement took place upon cleavage, since the residues at the cleavage site were separated by 69A in the cleaved structure but are covalently bonded in the uncleaved inhibitor. The structure of the similarly cleaved S variant (al AT-S*), along with the refinement of the normal cleaved M variant alAT*, was subsequently reported (3). These structures provided the basis for evaluation of serpin function (4), but still failed to provide a detailed structure of the active inhibitor form. To date, no such structure has been reported. The recently solved structures of noninhibitory conformations of other serpins (for a summary, see Table 1), including ovalbumin (5,6), the latent, noninhibitory form of plasminogen activator inhibitor 1 (7), unmodified antichymotrypsin (8), and antithrombin dimers (9,10), and a variety of experimental studies (11) provide clues for model ing aspects of the active form (12).
