5HKB
Crystal structure of the CFTR inhibitory factor Cif bound to the inhibitor KB2115
Summary for 5HKB
| Entry DOI | 10.2210/pdb5hkb/pdb |
| Related | 3KD2 4YX9 5HK9 5HKA |
| Descriptor | CFTR Inhibitory Factor (Cif), KB2115, ACETATE ION, ... (4 entities in total) |
| Functional Keywords | bacterial epoxide hydrolase, inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Pseudomonas aeruginosa UCBPP-PA14 |
| Total number of polymer chains | 4 |
| Total formula weight | 138843.53 |
| Authors | Hvorecny, K.L.,Madden, D.R. (deposition date: 2016-01-13, release date: 2016-05-18, Last modification date: 2024-11-06) |
| Primary citation | Kitamura, S.,Hvorecny, K.L.,Niu, J.,Hammock, B.D.,Madden, D.R.,Morisseau, C. Rational Design of Potent and Selective Inhibitors of an Epoxide Hydrolase Virulence Factor from Pseudomonas aeruginosa. J.Med.Chem., 59:4790-4799, 2016 Cited by PubMed Abstract: 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. PubMed: 27120257DOI: 10.1021/acs.jmedchem.6b00173 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.65 Å) |
Structure validation
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