Structure of PAI-1

The structure of intact, latent human plasminogen activator inhibitor-1 (PAI-1) has beensolved by single crystal x-ray diffraction to 2.6 Å resolution. PAI-1, the fast acting inhibitor of tissue plasminogen activator and urokinase, is a member of the serpin family of protease inhibitors. Serpins normally form very slow-dissociating complexes with their target proteases, but dissociate as cleaved species and fold into a highly stable inactive state in which the residues that flank the scissile bond (P1 and P1') are separated by ~70 Å. PAI-1 also spontaneously folds into a stable inactive state in the absence of cleavage; this state has been termed "latent" because inhibitory activity can be restored through denaturation and renaturation. The three-dimensional structure of latent PAI-1 reveals that residues on the N-terminal side of the primary recognition site are inserted as a central strand of the largest b-sheet, in positions similar to the corresponding residues in the cleaved form of the serpin a1-proteinase inhibitor (a1-PI). Residues C-terminal to the recognition site occupy positions on the surface of the molecule distinct from those of the corresponding residues in cleaved serpins or in the intact, inactive, serpin homolog ovalbumin and its cleavage product, plakalbumin. The structure of latent PAI-1 is similar to one formed after cleavage in other serpins, and the stability of both latent PAI-1 and cleaved serpins may be derived from the same structural features.