1.8-ANGSTROM CRYSTAL-STRUCTURE OF THE CATALYTIC DOMAIN OF HUMAN NEUTROPHIL COLLAGENASE (MATRIX METALLOPROTEINASE-8) COMPLEXED WITH A PEPTIDOMIMETIC HYDROXAMATE PRIME-SIDE INHIBITOR WITH A DISTINCT SELECTIVITY PROFILE

Matrix metalloproteinases (MMP) are zinc endopeptidases involved in ti ssue remodelling. They have been implicated in a series of pathologies , including cancer, arthritis, joint destruction and Alzheimer's disea se. Human neutrophil collagenase represents one of the three interstit ial collagenases that cleave triple-helical collagen of type I, II and III. Its catalytic domain (residues Phe79-Gly242) has been heterologo usly expressed in Escherichia coli and crystallized as a non-covalent complex with the hydroxamate inhibitor BB-1909, which has distinct sel ectivity against different MMP, in a crystal form. The crystal structu re, refined to 0.18-nm resolution, shows that BB-1909 is a right-hand- side inhibitor that binds to the S-1'-S-3' subsites and coordinates to the catalytic Zn2+ in a bidentate manner via the hydroxyl and carbony l oxygen atoms of the hydroxamate group in a similar manner to batimas tat. The collagenase/BB-1909 complex is described in detail and compar ed with the collagenase/batimastat complex. These studies provide info rmation on MMP specificity and thus may assist the development of more -selective MMP inhibitors.