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 tissue remodelling. They have been implicated in a series of pathologies, including cancer, arthritis, joint destruction and Alzheimer's disease. Human neutrophil collagenase represents one of the three interstitial collagenases that cleave triple-helical collagen of type I, II and III. Its catalytic domain (residues Phe79-Gly242) has been heterologously expressed in Escherichia coli and crystallized as a non-covalent complex with the hydroxamate inhibitor BB-1909, which has distinct selectivity against different MMP, in a crystal form. The crystal structure, 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 carbonyl oxygen atoms of the hydroxamate group in a similar manner to batimastat. The collagenase/BB-1909 complex is described in detail and compared with the collagenase/batimastat complex. These studies provide information on MMP specificity and thus may assist the development of more-selective MMP inhibitors.