1.8-A 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.
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 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.
Betz
M
M
Max-Planck-Institut für Biochemie, Abteilung Strukturforschung, Planegg-Martinsried, Germany.
Huxley
P
P
Davies
S J
SJ
Mushtaq
Y
Y
Pieper
M
M
Tschesche
H
H
Bode
W
W
Gomis-Rüth
F X
FX
D017364:Collagenases / Q000737:chemistry*; D003461:Crystallography; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D020784:Matrix Metalloproteinase 8; D061965:Matrix Metalloproteinase Inhibitors; D009504:Neutrophils / Q000201:enzymology*; D010446:Peptide Fragments / Q000737:chemistry*; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000737:chemistry; D011480:Protease Inhibitors / Q000737:chemistry*; D013876:Thiophenes / Q000737:chemistry
D061965:Matrix Metalloproteinase Inhibitors; D010446:Peptide Fragments; D011480:Protease Inhibitors; D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat; D017364:Collagenases; D020784:Matrix Metalloproteinase 8