3LIL
Human MMP12 in complex with non-zinc chelating inhibitor
Summary for 3LIL
| Entry DOI | 10.2210/pdb3lil/pdb |
| Related | 3LIK 3LIR 3LJG |
| Related PRD ID | PRD_000803 |
| Descriptor | Macrophage metalloelastase, ZINC ION, CALCIUM ION, ... (6 entities in total) |
| Functional Keywords | mmp12 elastase non-chelating inhibitor, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 18526.79 |
| 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 citation | Devel, 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: 20817735DOI: 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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