MECHANISM OF INHIBITION OF THE HUMAN MATRIX METALLOPROTEINASE STROMELYSIN-1 BY TIMP-1

Matrix metalloproteinases (MMPs) are zinc endopeptidases that are requ ired for the degradation of extracellular matrix components during nor mal embryo development, morphogenesis and tissue remodelling(1). Their proteolytic activities are precisely regulated by endogenous tissue i nhibitors of metalloproteinases (TIMPs)(1-5). Disruption of this balan ce results in diseases such as arthritis, atherosclerosis, tumour grow th and metastasis(1,2). Here we report the crystal structure of an MMP -TIMP complex formed between the catalytic domain of human stromelysin -1 (MMP-3) and human TIMP-1. TIMP-1, a 184-residue protein(5), has the shape of an elongated, contiguous wedge. With its long edge, consisti ng of five different chain regions, it occupies the entire length of t he active-site cleft of MMP-3. The central disulphide-linked segments Cys 1-Thr 2-Cys 3-Val 4 and Ser 68-Val 69 bind to either side of the c atalytic zinc. Cys 1 bidentally coordinates this zinc, and the Thr-2 s ide chain extends into the large specificity pocket of MMP-3. This unu sual architecture of the interface between MMP-3 and TIMP-1 suggests n ew possibilities for designing TIMP variants and synthetic MMP inhibit ors with potential therapeutic applications.