Crystal structures of the two major aggrecan degrading enzymes, ADAMTS4 and ADAMTS5.
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.
Department of Chemical and Screening Sciences, Wyeth Research, Cambridge, MA 02140, USA. lmosyak@wyeth.com
Lidia
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Mosyak
Katy
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Georgiadis
Tania
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Shane
Kristine
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Svenson
Tracy
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Hebert
Thomas
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McDonagh
Stewart
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Mackie
Stephane
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Olland
Laura
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Lin
Xiaotian
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Zhong
Ronald
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Kriz
Erica L
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Reifenberg
Lisa A
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Collins-Racie
Christopher
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Corcoran
Bethany
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Freeman
Richard
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Zollner
Tod
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Marvell
Matthew
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Vera
Phaik-Eng
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Sum
Edward R
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Lavallie
Mark
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Stahl
William
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Somers
D051722:ADAM Proteins / Q000737:chemistry*; D000071121:ADAMTS4 Protein; D000071116:ADAMTS5 Protein; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D011348:Procollagen N-Endopeptidase / Q000737:chemistry*; D011487:Protein Conformation
D004791:Enzyme Inhibitors; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein; C000603918:ADAMTS4 protein, human