Summary
PDB 3LIR deposited: 2010-01-25 modified: 2010-12-08
Title Human MMP12 in complex with non-zinc chelating inhibitor
Authors Beau, F., Czarny, B., Devel, L., Dive, V., Garcia, S., Georgiadis, D., LaJeunesse, E., Stura, E., Vera, L.
Method X-RAY DIFFRACTION
Structure factors resolution 1.9 rfactor 0.1586 rfree 0.2105
DPI 0.36 theoretical min: 0.15
Related PDB Entries 3LIK 3LIL 3LJG
Citations

After the disappointment of clinical trials with early broad spectrum synthetic inhibitors of matrix metalloproteinases (MMPs), the field is now resurging with a new focus on the development of selective inhibitors that fully discriminate between different members of the MMP family with several therapeutic applications in perspective. Here, we report a novel class of highly selective MMP-12 inhibitors, without a phosphinic zinc-binding group, designed to plunge deeper into the S(1)' cavity of the enzyme. The best inhibitor from this series, identified through a systematic chemical exploration, displays nanomolar potency toward MMP-12 and selectivity factors that range between 2 and 4 orders of magnitude toward a large set of MMPs. Comparison of the high resolution x-ray structures of MMP-12 in free state or bound to this new MMP-12 selective inhibitor reveals that this compound fits deeply within the S(1)' specificity cavity, maximizing surface/volume ratios, without perturbing the S(1)' loop conformation. This is in contrast with highly selective MMP-13 inhibitors that were shown to select a particular S(1)' loop conformation. The search for such compounds that fit precisely to preponderant S(1)' loop conformation of a particular MMP may prove to be an alternative effective strategy for developing selective inhibitors of MMPs.

J.Biol.Chem. 2010 Nov; 285(46):35900-35909 doi:10.1074/jbc.M110.139634

Cross References
Database source Identifier Description
PubMed 20817735 JBCHA3
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
3LIR/0 3LIR 0 monomer 0 1 7 1405