1.8‐Å Crystal Structure of the Catalytic Domain of Human Neutrophil Collagenase (Matrix Metalloproteinase‐8) Complexed with a Peptidomimetic Hydroxamate Primed‐Side Inhibitor with a Distinct Selectivity Profile

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Abstract
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 heterol‐ogously 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 S1′–S3′ 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.