MECHANISMS CONTRIBUTING TO THE CONFORMATIONAL AND FUNCTIONAL FLEXIBILITY OF PLASMINOGEN-ACTIVATOR INHIBITOR-1

Plasminogen activator inhibitor-1 (PAl-1) is unique among the serine p roteinase inhibitors (serpins) in that it can adopt at least three dif ferent conformations (active, substrate and latent). We report the X-r ay structure of a cleaved substrate variant of human PAl-1, which has a new beta-strand s4A formed by insertion of the amino-terminal portio n-of the reactive-site loop into beta-sheet A subsequent to cleavage. This is in contrast to the previous suggestion that-the non-inhibitory function of substrate-type serpins is mainly due to an inability of t he reactive-site loop to adopt this conformation. Comparison with the structure of latent PAl-1 provides insights into the molecular determi nants responsible for the transition of the stressed active conformati on to the thermostable latent conformation.