Structural basis of latency in plasminogen activator inhibitor-1

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Abstract
HUMAN plasminogen activator inhibitor-1 (PAI-1)1,2 is the fast-acting inhibitor of tissue plasminogen activator and urokinase3 and is a member of the serpin family of protease inhibitors4. Serpins normally form complexes with their target proteases that dissociate very slowly as cleaved species and then fold into a highly stable inactive state5 in which the residues that flank the scissile bond (P1 and P1'; ref. 6) are separated by about 70 Å (refs 7–9). PAI-1 also spontaneously folds into a stable10 inactive state without cleavage; this state is termed 'latent' because inhibitory activity can be restored through denaturation and renaturation2,10. Here we report the structure of intact latent PAI-1 determined by single-crystal X-ray diffraction to 2.6 Å resolution. The three-dimensional structure reveals that residues on the N-terminal side of the primary recognition site are inserted as a central strand of the largest βsheet, in positions similar to the corresponding residues in the cleaved form of the serpin α1proteinase inhibitor (α1-PI)7. Residues C-terminal to the recognition site occupy positions on the surface of the molecule distinct from those of the corresponding residues in cleaved serpins7–9 or in the intact inactive serpin homologue, ovalbumin11, and its cleavage product, plakal-bumin12. 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 features13,14.