Structural basis of the endoproteinase-protein inhibitor interaction

Proteolytic enzymes are potentially hazardous to their protein environment, so that their activity must be carefully controlled. Living organisms use protein inhibitors as a major tool to regulate the proteolytic activity of proteinases. Most of the inhibitors for which 3D structures are available a re directed towards serine proteinases, interacting with the active sites i n a 'canonical' i.e. substrate-like manner via an exposed reactive site loo p of conserved conformation. More recently, some non-canonically binding se rine proteinase inhibitors directed against coagulation factors, in particu lar thrombin, a few cysteine proteinase inhibitors inhibitory towards papai n-like proteinases, and three zinc endopeptidase inhibitors directed agains t metzincins and thermolysin have been characterised in the free and comple xed state, displaying novel mechanisms of inhibition with their target prot einases. These different interaction modes are presented and briefly discus sed with respect to the different strategies applied by nature. (C) 2000 El sevier Science B.V. All rights reserved.