Crystal structures of MMP-1 and -13 reveal the structural basis for selectivity
of collagenase inhibitors
Brett Lovejoy, Anthony R. Welch, Steven Carr, Christine Luong, Chris Broka, R. Than Hendricks, Jeffery A. Campbell, Keith A.M. Walker, Robert Martin, Harold Van Wart
& Michelle F. Browner
Inflammatory Diseases Unit, Roche Bioscience, Palo Alto, California 94304, USA.
The X-ray crystal structures of the catalytic domain of human collagenase-3
(MMP-13) and collagenase-1 (MMP-1) with bound inhibitors provides a basis
for understanding the selectivity profile of a novel series of matrix metalloprotease
(MMP) inhibitors. Differences in the relative size and shape of the MMP S1'
pockets suggest that this pocket is a critical determinant of MMP inhibitor
selectivity. The collagenase-3 S1' pocket is long and open, easily accommodating
large P1' groups, such as diphenylether. In contrast, the collagenase-1 S1'
pocket must undergo a conformational change to accommodate comparable P1'
groups. The selectivity of the diphenylether series of inhibitors for collagenase-3
is largely determined by their affinity for the preformed S1' pocket of collagenase-3,
as compared to the induced fit in collagenase-1.
