6P8T

Acinetobacter baumannii tRNA synthetase in complex with compound 1

6P8T の概要

• エントリーDOI: 10.2210/pdb6p8t/pdb
• 分子名称: Phenylalanine--tRNA ligase beta subunit, Phenylalanine--tRNA ligase alpha subunit, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: inhibitor, aminoacyl-trna synthetase, phers, antibacterial, ligase
• 由来する生物種: Acinetobacter baumannii (strain ATCC 19606 / DSM 30007 / CIP 70.34 / JCM 6841 / NBRC 109757 / NCIMB 12457 / NCTC 12156 / 81); 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 500977.78

構造登録者

Kahne, D.,Baidin, V.,Owens, T.W. (登録日: 2019-06-07, 公開日: 2020-11-18, 最終更新日: 2023-10-11)

主引用文献

Baidin, V.,Owens, T.W.,Lazarus, M.B.,Kahne, D.
Simple Secondary Amines Inhibit Growth of Gram-Negative Bacteria through Highly Selective Binding to Phenylalanyl-tRNA Synthetase.
J.Am.Chem.Soc., 143:623-627, 2021

PubMed Abstract: Antibiotics to treat drug-resistant Gram-negative infections are urgently needed but challenging to discover. Using a cell-based screen, we identified a simple secondary amine that inhibited the growth of wild-type and but not the growth of the Gram-positive organism . Resistance mutations in and mapped exclusively to the aminoacyl-tRNA synthetase PheRS. We confirmed biochemically that the compound inhibited PheRS from these organisms and showed that it did not inhibit PheRS from or humans. To understand the basis for the compound's high selectivity for only some PheRS enzymes, we solved crystal structures of and PheRS complexed with the inhibitor. The structures showed that the compound's benzyl group mimics the benzyl of phenylalanine. The other amine substituent, a 2-(cyclohexen-1-yl)ethyl group, induces a hydrophobic pocket in which it binds. Through bioinformatic analysis and mutagenesis, we show that the ability to induce a complementary hydrophobic pocket that can accommodate the second substituent explains the high selectivity of this remarkably simple molecular scaffold for Gram-negative PheRS. Because this secondary amine scaffold is active against wild-type Gram-negative pathogens but is not cytotoxic to mammalian cells, we suggest that it may be possible to develop it for use in combination antibiotic therapy to treat Gram-negative infections.

PubMed: 33411531
DOI: 10.1021/jacs.0c11113

実験手法

X-RAY DIFFRACTION (3.15 Å)