4K2F

Structure of Pseudomonas aeruginosa PvdQ bound to BRD-A08522488

4K2F の概要

• エントリーDOI: 10.2210/pdb4k2f/pdb
• 関連するPDBエントリー: 3SRA 3SRB 3SRC 4K2G
• 分子名称: Acyl-homoserine lactone acylase PvdQ, 1,2-ETHANEDIOL, (2S)-(4-chlorophenyl)(6-chloropyridin-2-yl)ethanenitrile, ... (5 entities in total)
• 機能のキーワード: amidohydrolase, bacterial protein, catalytic domain, high-throughput screening assays, molecular sequence data, oligopeptides, small molecule libraries, structure-activity relationship, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Pseudomonas aeruginosa; 詳細
• 細胞内の位置: Periplasm (Probable): Q9I194 Q9I194
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 79966.64

構造登録者

Drake, E.J.,Wurst, J.M.,Theriault, J.R.,Munoz, B.,Gulick, A.M. (登録日: 2013-04-09, 公開日: 2014-06-18, 最終更新日: 2024-11-06)

主引用文献

Wurst, J.M.,Drake, E.J.,Theriault, J.R.,Jewett, I.T.,VerPlank, L.,Perez, J.R.,Dandapani, S.,Palmer, M.,Moskowitz, S.M.,Schreiber, S.L.,Munoz, B.,Gulick, A.M.
Identification of Inhibitors of PvdQ, an Enzyme Involved in the Synthesis of the Siderophore Pyoverdine.
Acs Chem.Biol., 9:1536-1544, 2014

PubMed Abstract: Pseudomonas aeruginosa produces the peptide siderophore pyoverdine, which is used to acquire essential Fe(3+) ions from the environment. PvdQ, an Ntn hydrolase, is required for the biosynthesis of pyoverdine. PvdQ knockout strains are not infectious in model systems, suggesting that disruption of siderophore production via PvdQ inhibition could be exploited as a target for novel antibacterial agents, by preventing cells from acquiring iron in the low iron environments of most biological settings. We have previously described a high-throughput screen to identify inhibitors of PvdQ that identified inhibitors with IC50 values of ∼100 μM. Here, we describe the discovery of ML318, a biaryl nitrile inhibitor of PvdQ acylase. ML318 inhibits PvdQ in vitro (IC50 = 20 nM) by binding in the acyl-binding site, as confirmed by the X-ray crystal structure of PvdQ bound to ML318. Additionally, the PvdQ inhibitor is active in a whole cell assay, preventing pyoverdine production and limiting the growth of P. aeruginosa under iron-limiting conditions.

PubMed: 24824984
DOI: 10.1021/cb5001586

実験手法

X-RAY DIFFRACTION (1.99 Å)