Abstract
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.
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Acknowledgements
We thank C. Lopez-Otin for providing the cDNA for MMP-13, J. Barnett and S. Tsing for providing protein samples and all members of the MMP project team for helpful discussions.The Advanced Light Source is principally funded by the Office of Biological and Environmental Research of the Department of Energy with contributions from Lawrence Berkeley National Laboratory, Roche Bioscience, Amgen, University of California at Berkeley and Lawrence Livermore National Laboratory.
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Lovejoy, B., Welch, A., Carr, S. et al. Crystal structures of MMP-1 and -13 reveal the structural basis for selectivity of collagenase inhibitors. Nat Struct Mol Biol 6, 217–221 (1999). https://doi.org/10.1038/6657
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DOI: https://doi.org/10.1038/6657
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