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 processes including metastasis, joint destruction, and neurodegeneration, Human neutrophil collagenase (HNC, MMP-8) represents one of the three ''interstitial'' collagenases that cleave triple-helical collagens types I, II, and III. Its 163-residue catalytic domain (Met80 to Gly242) has been expressed in Escherichia coli and crystallized as a noncovalent complex with the hydroxamate inhibitor batimastat. The crystal structure, refined to 2.1 Angstrom, demonstrates that batimastat binds to the S1-S2' sites and coordinates to the catalytic zinc in a bidentate manner via the hydroxyl and carbonyl oxygens of the hydroxamate group. The batimastat-collagenase complex is described in detail, and the activities of batimastat analogues are discussed in the light of the protein-inhibitor interactions revealed by the crystallography studies,