5hka

Crystal structure of the CFTR inhibitory factor Cif bound to an amide inhibitor

spinqualitylabelsall models 5hka, resolution 2.05Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5hka is a 4 chain structure with sequence from Pseudomonas aeruginosa UCBPP-PA14. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.05Å Ligands: 64N Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A0A0H2ZD27_PSEAB Publication Abstract from PubMed The virulence factor cystic fibrosis transmembrane conductance regulator (CFTR) inhibitory factor (Cif) is secreted by Pseudomonas aeruginosa and is the founding member of a distinct class of epoxide hydrolases (EHs) that triggers the catalysis-dependent degradation of the CFTR. We describe here the development of a series of potent and selective Cif inhibitors by structure-based drug design. Initial screening revealed 1a (KB2115), a thyroid hormone analog, as a lead compound with low micromolar potency. Structural requirements for potency were systematically probed, and interactions between Cif and 1a were characterized by X-ray crystallography. On the basis of these data, new compounds were designed to yield additional hydrogen bonding with residues of the Cif active site. From this effort, three compounds were identified that are 10-fold more potent toward Cif than our first-generation inhibitors and have no detectable thyroid hormone-like activity. These inhibitors will be useful tools to study the pathological role of Cif and have the potential for clinical application. Rational Design of Potent and Selective Inhibitors of an Epoxide Hydrolase Virulence Factor from Pseudomonas aeruginosa.,Kitamura S, Hvorecny KL, Niu J, Hammock BD, Madden DR, Morisseau C J Med Chem. 2016 May 26;59(10):4790-9. doi: 10.1021/acs.jmedchem.6b00173. Epub, 2016 May 4. PMID:27120257 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also CFTR inhibitory factor

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