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Published online before print November 27, 2007, 10.1110/ps.073287008
Protein Science (2008), 17:16-21. Published by Cold Spring Harbor Laboratory Press. Copyright © 2008 The Protein Society
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ACCELERATED COMMUNICATION

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

Lidia Mosyak1, Katy Georgiadis2, Tania Shane1, Kristine Svenson1, Tracy Hebert1, Thomas McDonagh1, Stewart Mackie1, Stephane Olland1, Laura Lin1, Xiaotian Zhong1, Ronald Kriz1, Erica L. Reifenberg2, Lisa A. Collins-Racie3, Christopher Corcoran3, Bethany Freeman3, Richard Zollner3, Tod Marvell3, Matthew Vera1, Phaik-Eng Sum1, Edward R. Lavallie3, Mark Stahl1, and William Somers1

1 Department of Chemical and Screening Sciences, Wyeth Research, Cambridge, Massachusetts 02140, USA
2 Women's Health and Musculoskeletal Biology, Wyeth Research, Cambridge, Massachusetts 02140, USA
3 Department of Biological Technologies, Wyeth Research, Cambridge, Massachusetts 02140, USA

(RECEIVED October 10, 2007; FINAL REVISION October 15, 2007; ACCEPTED October 16, 2007)

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.

Keywords: protein structure; enzymes; metalloproteins; aggrecanases


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[Abstract] [Full Text] [PDF]


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