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