4gr8

Crystal structure of the catalytic domain of Human MMP12 in complex with selective phosphinic inhibitor RXP470C

spinqualitylabelsall models 4gr8, resolution 1.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4gr8 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CA, IMD, R4C, ZN 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 The molecular determinants responsible for the potency of the RXP470.1 phosphinic peptide inhibitor towards matrix metalloprotease-12 (MMP-12) remain elusive. To address this issue, structure-activity study, X-ray crystallography and isothermal titration calorimetry (ITC) experiments were performed. The crystal structure of MMP-12/inhibitor complex (1.15 A) reveals that the inhibitor establishes multiple interactions with the MMP-12 active site, with its long P1' side chain filling most part of the S1' deep cavity. ITC experiments indicate that the binding of this inhibitor to MMP-12 is mostly entropy driven (DeltaG degrees = -13.1 kcal/mol, DeltaH degrees = -2.53 kcal/mol and -TDeltaS degrees = -10.60 kcal/mol) and involves a proton uptake from the buffer. Comparing phosphinic versus hydroxamate inhibitors reveals that the chelation of the zinc ion is slightly different, leading the inhibitor backbone to adopt a position in which the hydrogen bonding with the MMP-12 active site is less favorable in phosphinic inhibitor, while maintaining high affinity. Molecular determinants of a selective matrix metalloprotease-12 inhibitor: Insights from crystallography and thermodynamic studies.,Czarny B, Stura EA, Devel L, Vera L, Lajeunesse E, Beau F, Calderone V, Fragai M, Luchinat C, Dive V J Med Chem. 2013 Jan 23. PMID:23343195 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Matrix metalloproteinase 3D structures

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