5HKA

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

5HKA の概要

• エントリーDOI: 10.2210/pdb5hka/pdb
• 関連するPDBエントリー: 3KD2 4YX9 5HK9 5HKB
• 分子名称: CFTR inhibitory factor, 5'-[2,6-dichloro-4-(propanoylamino)phenoxy]-2'-hydroxybiphenyl-4-carboxamide (3 entities in total)
• 機能のキーワード: bacterial epoxide hydrolase, inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Pseudomonas aeruginosa (strain UCBPP-PA14)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 138439.98

構造登録者

Hvorecny, K.L.,Madden, D.R. (登録日: 2016-01-13, 公開日: 2016-05-18, 最終更新日: 2024-11-20)

主引用文献

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

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: 27120257
DOI: 10.1021/acs.jmedchem.6b00173

実験手法

X-RAY DIFFRACTION (2.05 Å)