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.
Mosyak
Lidia
L
Department of Chemical and Screening Sciences, Wyeth Research, Cambridge, MA 02140, USA. lmosyak@wyeth.com
Georgiadis
Katy
K
Shane
Tania
T
Svenson
Kristine
K
Hebert
Tracy
T
McDonagh
Thomas
T
Mackie
Stewart
S
Olland
Stephane
S
Lin
Laura
L
Zhong
Xiaotian
X
Kriz
Ronald
R
Reifenberg
Erica L
EL
Collins-Racie
Lisa A
LA
Corcoran
Christopher
C
Freeman
Bethany
B
Zollner
Richard
R
Marvell
Tod
T
Vera
Matthew
M
Sum
Phaik-Eng
PE
Lavallie
Edward R
ER
Stahl
Mark
M
Somers
William
W
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