6ekn

Crystal structure of MMP12 in complex with inhibitor BE7.

spinqualitylabelsall models 6ekn, resolution 1.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6ekn is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: B9N, CA, EDO, ZN Gene: MMP12, HME (HUMAN) Activity: Macrophage elastase, with EC number 3.4.24.65 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [MMP12_HUMAN] May be involved in tissue injury and remodeling. Has significant elastolytic activity. Can accept large and small amino acids at the P1' site, but has a preference for leucine. Aromatic or hydrophobic residues are preferred at the P1 site, with small hydrophobic residues (preferably alanine) occupying P3. Publication Abstract from PubMed 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 identify a sulfide, 4a, bearing a N-1-hydroxypiperidine-2,6-dione (HPD) group as new ZBG. 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 Zn2+ 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. Development of Thioaryl-based Matrix Metalloproteinase-12 Inhibitors with Alternative Zinc-Binding Groups: Synthesis, Potentiometric, NMR and Crystallographic Studies.,Nuti E, Cuffaro D, Bernardini E, Camodeca C, Panelli L, Chaves S, Ciccone L, Tepshi L, Vera L, Orlandini E, Nencetti S, Stura EA, Santos MA, Dive V, Rossello A J Med Chem. 2018 May 4. doi: 10.1021/acs.jmedchem.8b00096. PMID:29727184 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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