4P74

PheRS in complex with compound 3a

4P74 の概要

• エントリーDOI: 10.2210/pdb4p74/pdb
• 関連するPDBエントリー: 4P71 4P72 4P73 4P75
• 分子名称: Phenylalanine--tRNA ligase beta subunit, Phenylalanine--tRNA ligase alpha subunit, N-[(3S)-1,1-dioxidotetrahydrothiophen-3-yl]-2-[(4-methylphenoxy)methyl]-1,3-thiazole-4-carboxamide, ... (4 entities in total)
• 機能のキーワード: phenylalanine trna synthetase, phers, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• 由来する生物種: Pseudomonas aeruginosa; 詳細
• 細胞内の位置: Cytoplasm : Q9I0A4 Q9I0A3
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 250760.39

構造登録者

Ferguson, A.D. (登録日: 2014-03-25, 公開日: 2014-06-25, 最終更新日: 2023-09-27)

主引用文献

Abibi, A.,Ferguson, A.D.,Fleming, P.R.,Gao, N.,Hajec, L.I.,Hu, J.,Laganas, V.A.,McKinney, D.C.,McLeod, S.M.,Prince, D.B.,Shapiro, A.B.,Buurman, E.T.
The role of a novel auxiliary pocket in bacterial phenylalanyl-tRNA synthetase druggability.
J.Biol.Chem., 289:21651-21662, 2014

PubMed Abstract: The antimicrobial activity of phenyl-thiazolylurea-sulfonamides against Staphylococcus aureus PheRS are dependent upon phenylalanine levels in the extracellular fluids. Inhibitor efficacy in animal models of infection is substantially diminished by dietary phenylalanine intake, thereby reducing the perceived clinical utility of this inhibitor class. The search for novel antibacterial compounds against Gram-negative pathogens led to a re-evaluation of this phenomenon, which is shown here to be unique to S. aureus. Inhibition of macromolecular syntheses and characterization of novel resistance mutations in Escherichia coli demonstrate that antimicrobial activity of phenyl-thiazolylurea-sulfonamides is mediated by PheRS inhibition, validating this enzyme as a viable drug discovery target for Gram-negative pathogens. A search for novel inhibitors of PheRS yielded three novel chemical starting points. NMR studies were used to confirm direct target engagement for phenylalanine-competitive hits. The crystallographic structure of Pseudomonas aeruginosa PheRS defined the binding modes of these hits and revealed an auxiliary hydrophobic pocket that is positioned adjacent to the phenylalanine binding site. Three viable inhibitor-resistant mutants were mapped to this pocket, suggesting that this region is a potential liability for drug discovery.

PubMed: 24936059
DOI: 10.1074/jbc.M114.574061

実験手法

X-RAY DIFFRACTION (2.7 Å)