Crystal structures of MMP-1 and -13 reveal the structural basis for selectivity of collagenase inhibitors

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 metal loprotease (MMP) inhibitors. Differences in the relative size and shape of the MMP S1' pockets suggest that this pocket is a critical determinant of M MP inhibitor selectivity. The collagenase-3 S1' pocket is long and open, ea sily accommodating large P1' groups, such as diphenylether, In contrast, th e collagenase-1 S1' pocket must undergo a conformational change to accommod ate comparable P1' groups. The selectivity of the diphenylether series of i nhibitors for collagenase-3 is largely determined by their affinity for the preformed S1' pocket of collagenase-3, as compared to the induced fit in c ollagenase-1.