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Crystal structures of the two major aggrecan degrading enzymes, ADAMTS4 and ADAMTS5
Author(s) -
Mosyak Lidia,
Georgiadis Katy,
Shane Tania,
Svenson Kristine,
Hebert Tracy,
McDonagh Thomas,
Mackie Stewart,
Olland Stephane,
Lin Laura,
Zhong Xiaotian,
Kriz Ronald,
Reifenberg Erica L.,
CollinsRacie Lisa A.,
Corcoran Christopher,
Freeman Bethany,
Zollner Richard,
Marvell Tod,
Vera Matthew,
Sum PhaikEng,
Lavallie Edward R.,
Stahl Mark,
Somers William
Publication year - 2008
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1110/ps.073287008
Subject(s) - aggrecanase , aggrecan , chemistry , active site , gene isoform , enzyme , crystal structure , biochemistry , stereochemistry , crystallography , osteoarthritis , articular cartilage , gene , medicine , alternative medicine , pathology
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.