Structural and inhibition analysis reveals the mechanism of selectivity of a series of aggrecanase inhibitors.
Several inhibitors of a series of cis-1(S)2(R)-amino-2-indanol-based compounds were reported to be selective for the aggrecanases, ADAMTS-4 and -5 over other metalloproteases. To understand the nature of this selectivity for aggrecanases, the inhibitors, along with the broad spectrum metalloprotease inhibitor marimastat, were independently bound to the catalytic domain of ADAMTS-5, and the corresponding crystal structures were determined. By comparing the structures, it was determined that the specificity of the relative inhibitors for ADAMTS-5 was not driven by a specific interaction, such as zinc chelation, hydrogen bonding, or charge interactions, but rather by subtle and indirect factors, such as water bridging, ring rigidity, pocket size, and shape, as well as protein conformation flexibility.
Tortorella
Micky D
MD
Pfizer Global Research and Development, St. Louis, Missouri 63017, USA. micky.d.tortorella@gmail.com
Tomasselli
Alfredo G
AG
Mathis
Karl J
KJ
Schnute
Mark E
ME
Woodard
Scott S
SS
Munie
Grace
G
Williams
Jennifer M
JM
Caspers
Nicole
N
Wittwer
Arthur J
AJ
Malfait
Anne-Marie
AM
Shieh
Huey-Sheng
HS
D051722:ADAM Proteins / Q000737:chemistry; D000071121:ADAMTS4 Protein; D000071116:ADAMTS5 Protein; D000818:Animals; D002417:Cattle; D010450:Endopeptidases / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D011348:Procollagen N-Endopeptidase / Q000737:chemistry; D017434:Protein Structure, Tertiary; D040681:Structural Homology, Protein; D015032:Zinc / Q000737:chemistry
D004791:Enzyme Inhibitors; D010450:Endopeptidases; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein; C000603918:ADAMTS4 protein, human; C083641:aggrecanase; D015032:Zinc