Crystal structures of the two major aggrecan degrading enzymes, ADAMTS4 and ADAMTS5.
Article Details
- CitationCopy to clipboard
Mosyak L, Georgiadis K, Shane T, Svenson K, Hebert T, McDonagh T, Mackie S, Olland S, Lin L, Zhong X, Kriz R, Reifenberg EL, Collins-Racie LA, Corcoran C, Freeman B, Zollner R, Marvell T, Vera M, Sum PE, Lavallie ER, Stahl M, Somers W
Crystal structures of the two major aggrecan degrading enzymes, ADAMTS4 and ADAMTS5.
Protein Sci. 2008 Jan;17(1):16-21. Epub 2007 Nov 27.
- PubMed ID
- 18042673 [ View in PubMed]
- Abstract
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.