Crystal structures of the two major aggrecan degrading enzymes, ADAMTS4 and ADAMTS5

被引：109

作者：

Mosyak, Lidia ^{[1
]}

Georgiadis, Katy ^{[2
]}

Shane, Tania ^{[1
]}

Svenson, Kristine ^{[1
]}

Hebert, Tracy ^{[1
]}

Mcdonagh, Thomas ^{[1
]}

Mackie, Stewart ^{[1
]}

Olland, Stephane ^{[1
]}

Lin, Laura ^{[1
]}

Zhong, Xiaotian ^{[1
]}

Kriz, Ronald ^{[1
]}

Reifenberg, Erica L. ^{[2
]}

Collins-Racie, Lisa A. ^{[3
]}

Corcoran, Christopher ^{[3
]}

Freeman, Bethany ^{[3
]}

Zollner, Richard ^{[3
]}

Marvell, Tod ^{[3
]}

Vera, Matthew ^{[1
]}

Sum, Phaik-Eng ^{[1
]}

Lavallie, Edward R. ^{[3
]}

Stahl, Mark ^{[1
]}

Somers, William ^{[1
]}

机构：

[1] Wyeth Ayerst Res, Dept Chem & Screening Sci, Cambridge, MA 02140 USA

[2] Wyeth Ayerst Res, Womens Hlth & Musculoskeletal Biol, Cambridge, MA 02140 USA

[3] Wyeth Ayerst Res, Dept Biol Technol, Cambridge, MA 02140 USA

来源：

PROTEIN SCIENCE | 2008年 / 17卷 / 01期

关键词：

protein structure; enzymes; metalloproteins; aggrecanases;

D O I：

10.1110/ps.073287008

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 [生物化学与分子生物学]; 081704 [应用化学];

摘要：

Aggrecanases are now believed to be the principal proteinases responsible for aggrecan degradation in osteoarthritis. Given their potential as a drug target, we solved crystal structures of the two most active human aggrecanase isoforms, ADAMTS4 and ADAMTS5, each in complex with bound inhibitor and one wherein the enzyme is in apo form. These structures show that the unliganded and inhibitor-bound enzymes exhibit two essentially different catalytic-site configurations: an autoinhibited, nonbinding, closed form and an open, binding form. On this basis, we propose that mature aggrecanases exist as an ensemble of at least two isomers, only one of which is proteolytically active.

引用

页码：16 / 21

页数：6

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