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 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.
Grams
F
F
Abteilung für Strukturforschung, Max-Planck-Institut für Biochemie, Martinsried, Germany.
Crimmin
M
M
Hinnes
L
L
Huxley
P
P
Pieper
M
M
Tschesche
H
H
Bode
W
W
D000595:Amino Acid Sequence; D017364:Collagenases / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D006877:Hydroxamic Acids / Q000037:antagonists & inhibitors*; D020784:Matrix Metalloproteinase 8; D008969:Molecular Sequence Data; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D013237:Stereoisomerism; D013876:Thiophenes / Q000737:chemistry* / Q000378:metabolism
D006877:Hydroxamic Acids; D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat; D017364:Collagenases; D020784:Matrix Metalloproteinase 8