1utz

File:1utz.gif

spinqualitylabelsall models 1utz, resolution 2.5Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

CRYSTAL STRUCTURE OF MMP-12 COMPLEXED TO (2R)-3-({[4-[(PYRI DIN-4-YL)PHENYL]-THIEN-2-YL}CARBOXAMIDO)(PHENYL)PROPANOIC ACID

OverviewOverview

Human macrophage elastase (MMP-12) plays an important role in inflammatory, processes and has been implicated in diseases such as emphysema and, chronic obstructive pulmonary disease (COPD). It is therefore an, attractive target for therapeutic agents. As part of a structure-based, drug design programme to find new inhibitors of MMP-12, the crystal, structures of the MMP-12 catalytic domain (residues 106-268) complexed to, three different non-peptidic small molecule inhibitors have been, determined. The structures reveal that all three ligands bind in the S1', pocket but show varying degrees of interaction with the Zn atom. The, structures of the complexes with inhibitors CP-271485 and PF-00356231, reveal that their central morpholinone and thiophene rings, respectively, sit over the Zn atom at a distance of approximately 5A, locating the, inhibitors halfway down the S1' pocket. In both of these structures, an, acetohydroxamate anion, an artefact of the crystallisation solution, chelates the zinc atom. By contrast, the acetohydroxamate anion is, displaced by the ligand in the structure of MMP-12 complexed to PD-0359601, (Bayer), a potent zinc chelating N-substituted biaryl butyric acid, used, as a reference compound for crystallisation. Although a racemate was used, for the crystallisation, the S enantiomer only is bound in the crystal., Important hydrophobic interactions between the inhibitors and residues, from the S1' pocket are observed in all of the structures. The relative, selectivity displayed by these ligands for MMP-12 over other MMP family, members is discussed.

About this StructureAbout this Structure

1UTZ is a Single protein structure of sequence from Homo sapiens with ZN, CA, PF3 and HAE as ligands. Active as Macrophage elastase, with EC number 3.4.24.65 Structure known Active Site: ZN2. Full crystallographic information is available from OCA.

ReferenceReference

Crystal structures of novel non-peptidic, non-zinc chelating inhibitors bound to MMP-12., Morales R, Perrier S, Florent JM, Beltra J, Dufour S, De Mendez I, Manceau P, Tertre A, Moreau F, Compere D, Dublanchet AC, O'Gara M, J Mol Biol. 2004 Aug 20;341(4):1063-76. PMID:15289103

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