PDB 3LIK 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.
Structure factors resolution 1.8 rfactor 0.1574 rfree 0.2093
DPI 0.35 theoretical min: 0.13
Related PDB Entries 3LIL 3LIR 3LJG

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
3LIK/0 3LIK 0 monomer 0 1 10 1406