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3LIK

Human MMP12 in complex with non-zinc chelating inhibitor

Summary for 3LIK
Entry DOI10.2210/pdb3lik/pdb
Related1RMZ 3LIL 3LIR 3LJG
Related PRD IDPRD_001058
DescriptorMacrophage metalloelastase, ZINC ION, CALCIUM ION, ... (7 entities in total)
Functional Keywordsmmp12 elastase non-chelating inhibitor, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
Biological sourceHomo sapiens (human)
Cellular locationSecreted, extracellular space, extracellular matrix (Probable): P39900
Total number of polymer chains1
Total formula weight19354.42
Authors
Stura, E.A.,Dive, V.,Devel, L.,Czarny, B.,Vera, L.,Beau, F. (deposition date: 2010-01-25, release date: 2010-09-01, Last modification date: 2023-09-06)
Primary citationDevel, L.,Garcia, S.,Czarny, B.,Beau, F.,LaJeunesse, E.,Vera, L.,Georgiadis, D.,Stura, E.,Dive, V.
Insights from selective non-phosphinic inhibitors of MMP-12 tailored to fit with an S1' loop canonical conformation.
J.Biol.Chem., 285:35900-35909, 2010
Cited by
PubMed Abstract: 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.
PubMed: 20817735
DOI: 10.1074/jbc.M110.139634
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.8 Å)
Structure validation

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