STRUCTURE OF THE CATALYTIC DOMAIN OF HUMAN FIBROBLAST COLLAGENASE COMPLEXED WITH AN INHIBITOR

In rheumatoid and osteoarthritis, degradation of articular cartilage i s mediated by the matrix metalloproteinases collagenase, stromelysin a nd gelatinase. The key event in this process is the cleavage of triple helical collagen by collagenase. We have determined the crystal struc ture of the catalytic domain of human recombinant fibroblast collagena se complexed with a synthetic inhibitor at 2.2 Angstrom resolution. Th e protein fold is similar to the amino termini of the zinc endopeptida ses astacin thermolysin and elastase despite a lack of primary sequenc e homology. The conformation of the bound inhibitor provides a molecul ar basis for the design of inhibitors of collagenase and other matrix metalloproteinases. Such inhibitors should be useful in the treatment of a variety of diseases including arthritis and cancer.