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

被引:75
作者
Betz, M
Huxley, P
Davies, SJ
Mushtaq, Y
Pieper, M
Tschesche, H
Bode, W
GomisRuth, FX
机构
[1] MAX PLANCK INST BIOCHEM, PLANEGG, GERMANY
[2] BRITISH BIOTECH PHARMACEUT LTD, OXFORD, ENGLAND
[3] UNIV BIELEFELD, D-4800 BIELEFELD, GERMANY
来源
EUROPEAN JOURNAL OF BIOCHEMISTRY | 1997年 / 247卷 / 01期
关键词
X-ray crystal structure; matrix metalloprotease; protein inhibitor complex; drug design;
D O I
10.1111/j.1432-1033.1997.00356.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:356 / 363
页数:8
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