MATRIX METALLOPROTEASES - VARIATIONS ON A THEME

The family of proteins called matrix metalloproteinases (MMPs) are a c lass of structurally related proteins that are collectively responsibl e for the metabolism of extracellular matrix proteins. These zinc and calcium dependent enzymes, which include the collagenases, stromelysin s and gelatinases, are involved in normal tissue remodelling processes such as wound healing, pregnancy and angiogenesis. Under physiologica l conditions, in addition to the regulated proteolyses of inactive pre cursors to the active form, the degradative nature of these enzymes ar e precisely controlled by endogenous inhibitors (TIMPs). The excess sy ntheses and production of these proteins lead to the accelerated matri x degradation associated with diseases such as arthritis, cancer and m ultiple sclerosis. The MMPs have therefore proved to be attractive tar gets for structure based drug design. The pursuit of low molecular wei ght inhibitors of these proteins have encouraged structural studies on several members of family, so that the molecular details of enzyme-in hibitor interactions of the MMPs have become available. These studies provide insights into the basic structural framework of the MMP superf amily and reveal characteristics which promote specificity between ind ividual members. The analyses of the three dimensional structure of th e MMPs in the context of their primary sequence and the design and sel ectivity of low molecular weight inhibitors of the superfamily is the subject of this review. (C) 1998 Elsevier Science Ltd. All rights rese rved.