9F8R

Crystal Structure of PhzA/B from Burkholderia cepacia R18194 in complex with (4-Chlorophenyl)[2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl]methanone

これはPDB形式変換不可エントリーです。

9F8R の概要

• エントリーDOI: 10.2210/pdb9f8r/pdb
• 関連するPDBエントリー: 9F8H 9F8I 9F8J 9F8K 9F8L 9F8M 9F8N 9F8O 9F8P 9F8Q 9F8S
• 分子名称: Phenazine biosynthesis protein A/B, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, 1,2-ETHANEDIOL, ... (6 entities in total)
• 機能のキーワード: pyocyanin, phenazine biosynthesis, virulence, inhibitor, ketosteroid-isomerase, cocrystal, phza/b, burkholderia cepacia, biosynthetic protein
• 由来する生物種: Burkholderia lata
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 88609.68

構造登録者

Zimmermann, M.,Thiemann, M.,Kunick, C.,Blankenfeldt, W. (登録日: 2024-05-06, 公開日: 2025-04-16)

主引用文献

Thiemann, M.,Zimmermann, M.,Diederich, C.,Zhan, H.,Lebedev, M.,Pletz, J.,Baumgarten, J.,Handke, M.,Musken, M.,Breinbauer, R.,Krasteva-Christ, G.,Zanin, E.,Empting, M.,Schiedel, M.,Kunick, C.,Blankenfeldt, W.
From Bones to Bugs: Structure-Based Development of Raloxifene-Derived Pathoblockers That Inhibit Pyocyanin Production in Pseudomonas aeruginosa.
J.Med.Chem., 68:7390-7420, 2025

PubMed Abstract: The human pathogen is particularly notorious for its multiple resistance mechanisms. A new concept for anti-infectives is the "pathoblocker" approach, which targets virulence factors to disarm rather than kill pathogens and thus attenuates the development of resistance. Based on the estrogen receptor modulator raloxifene, which had previously been identified as a potential biosynthesis inhibitor of the virulence factor pyocyanin screening, analogues have been developed as pathoblockers against . These compounds reduce the production of pyocyanin by binding to the phenazine biosynthesis enzyme PhzB. Structure-activity relationships (SAR) were explored using nano differential scanning fluorimetry, isothermal titration calorimetry, and 12 X-ray cocrystal structures. Compared to raloxifene, congener shows a 60-fold lower affinity for the human estrogen receptor with a 15-fold increase in pyocyanin inhibitory activity. The comprehensive structural information gathered in this study paves the way for the development of improved pathoblockers with increased potency and selectivity.

PubMed: 40156840
DOI: 10.1021/acs.jmedchem.4c03065

実験手法

X-RAY DIFFRACTION (1.58 Å)