Structure determination and analysis of human neutrophil collagenase complexed with a hydroxamate inhibitor

Abstract

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 A, 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.

Structure of malonic acid‐based inhibitors bound to human neutrophil collagenase. A new binding mode explains apparently anomalous data

“…Most of these mimic peptides and most likely bind analogous to the corresponding peptide substrates (Fig. l), as has been shown in several X-ray crystallographic studies Borkakoti et al, 1994;Lovejoy et al, 1994;Reinemer et al, 1994;Spurlino et al, 1994;Stams et al, 1994;Browner et al, 1995;Grams et al, 1995aGrams et al, , 1995bDhanaraj et ai., 1996). The generalized structures of most of these inhibitors have been previously described (Beckett et al, 1996;Fig.…”

Crystal Structure of the Catalytic Domain of MMP-16/MT3-MMP: Characterization of MT-MMP Specific Features

“…Both oxygen atoms, together with the three ligating His nitrogen atoms (Zn distances between 2.02 and 2.16 Ǻ), make up a trigonal-bipyramidal coordination sphere around this zinc ion. The peptide-like backbone is bound similar to that observed in the corresponding batimastat complex with MMP-8, 48 i.e. inserted between the bulge-edge strand and the wall-forming segment, under formation of five inter-main-chain hydrogen bonds (distances between 2.79 and 2.98 Ǻ).…”

Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment

“…An attractive aspect of inhibiting MMP activity in cancer is that the target of the anti-cancer therapy will include Initially, drugs were targeted to the chemical functional group that chelates the active site zinc(II) ion which is a ubiquitous feature of MMPs. Peptide and peptide-like compounds have been designed which combine backbone features (P1, P1', P2', p53' regions) which favorably interact with the enzyme subsites (S1, S1', S2', S3' pockets) and functionality capable of binding zinc (chelator) in the catalytic site (Gomis-Ruth et al, 1997;Grams et al, 1995). These drugs essentially mimic the collagen substrate of MMPs, and thereby work as competitive, potent, but reversible inhibitors of enzyme activity (Brown and Whitaker, 1999).…”