STRUCTURE DETERMINATION AND ANALYSIS OF HUMAN NEUTROPHIL COLLAGENASE COMPLEXED WITH A HYDROXAMATE INHIBITOR

Matrix metalloproteinases are a family of zinc endopeptidases involved in tissue remodeling. They have been implicated in various disease pr ocesses including metastasis, joint destruction, and neurodegeneration , Human neutrophil collagenase (HNC, MMP-8) represents one of the thre e ''interstitial'' collagenases that cleave triple-helical collagens t ypes I, II, and III. Its 163-residue catalytic domain (Met80 to Gly242 ) has been expressed in Escherichia coli and crystallized as a noncova lent complex with the hydroxamate inhibitor batimastat. The crystal st ructure, refined to 2.1 Angstrom, demonstrates that batimastat binds t o the S1-S2' sites and coordinates to the catalytic zinc in a bidentat e manner via the hydroxyl and carbonyl oxygens of the hydroxamate grou p. The batimastat-collagenase complex is described in detail, and the activities of batimastat analogues are discussed in the light of the p rotein-inhibitor interactions revealed by the crystallography studies,