6EKN
Crystal structure of MMP12 in complex with inhibitor BE7.
Summary for 6EKN
| Entry DOI | 10.2210/pdb6ekn/pdb |
| Descriptor | Macrophage metalloelastase, ZINC ION, CALCIUM ION, ... (6 entities in total) |
| Functional Keywords | metzincin, carboxylate inhibitor alternative zinc-binding groups, hydrolase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 18383.28 |
| Authors | Ciccone, L.,Tepshi, L.,Nuti, E.,Rossello, A.,Stura, E.A. (deposition date: 2017-09-26, release date: 2018-05-16, Last modification date: 2024-01-17) |
| Primary citation | Nuti, E.,Cuffaro, D.,Bernardini, E.,Camodeca, C.,Panelli, L.,Chaves, S.,Ciccone, L.,Tepshi, L.,Vera, L.,Orlandini, E.,Nencetti, S.,Stura, E.A.,Santos, M.A.,Dive, V.,Rossello, A. Development of Thioaryl-Based Matrix Metalloproteinase-12 Inhibitors with Alternative Zinc-Binding Groups: Synthesis, Potentiometric, NMR, and Crystallographic Studies. J. Med. Chem., 61:4421-4435, 2018 Cited by PubMed Abstract: Matrix metalloproteinase-12 (MMP-12) selective inhibitors could play a role in the treatment of lung inflammatory and cardiovascular diseases. In the present study, the previously reported 4-methoxybiphenylsulfonyl hydroxamate and carboxylate based inhibitors (1b and 2b) were modified to enhance their selectivity for MMP-12. In the newly synthesized thioaryl derivatives, the nature of the zinc binding group (ZBG) and the sulfur oxidation state were changed. Biological assays carried out in vitro on human MMPs with the resulting compounds led to identification of a sulfide, 4a, bearing an N-1-hydroxypiperidine-2,6-dione (HPD) group as new ZBG. Compound 4a is a promising hit compound since it displayed a nanomolar affinity for MMP-12 with a marked selectivity over MMP-9, MMP-1, and MMP-14. Solution complexation studies with Zn were performed to characterize the chelating abilities of the new compounds and confirmed the bidentate binding mode of HPD derivatives. X-ray crystallography studies using MMP-12 and MMP-9 catalytic domains were carried out to rationalize the biological results. PubMed: 29727184DOI: 10.1021/acs.jmedchem.8b00096 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.2 Å) |
Structure validation
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