9DFC

Crystal structure of the wild-type Thermus thermophilus 70S ribosome in complex with lasso peptide lariocidin, mRNA, aminoacylated A-site Phe-tRNAphe, aminoacylated P-site fMet-tRNAmet, and deacylated E-site tRNAphe at 2.50A resolution

これはPDB形式変換不可エントリーです。

9DFC の概要

• エントリーDOI: 10.2210/pdb9dfc/pdb
• 分子名称: 23S Ribosomal RNA, 50S ribosomal protein L14, 50S ribosomal protein L15, ... (62 entities in total)
• 機能のキーワード: lasso peptide; ripp; ribosome; antibiotic; trna; decoding; translocation; inhibitor; drug resistance, ribosome
• 由来する生物種: Escherichia coli; 詳細
• タンパク質・核酸の鎖数: 114
• 化学式量合計: 4574932.40

構造登録者

Aleksandrova, E.V.,Travin, D.Y.,Jangra, M.,Kaur, M.,Darwish, L.,Koteva, K.,Klepacki, D.,Wang, W.,Tiffany, M.,Sokaribo, A.,Coombes, B.K.,Vazquez-Laslop, N.,Wright, G.D.,Mankin, A.S.,Polikanov, Y.S. (登録日: 2024-08-29, 公開日: 2024-11-20)

主引用文献

Wright, G.,Jangra, M.,Travin, D.,Aleksandrova, E.,Kaur, M.,Darwish, L.,Koteva, K.,Klepacki, D.,Wang, W.,Tiffany, M.,Sokaribo, A.,Coombes, B.,Vazquez-Laslop, N.,Polikanov, Y.,Mankin, A.
A Broad Spectrum Lasso Peptide Antibiotic Targeting the Bacterial Ribosome.
Res Sq, 2024

PubMed Abstract: Lasso peptides, biologically active molecules with a distinct structurally constrained knotted fold, are natural products belonging to the class of ribosomally-synthesized and posttranslationally modified peptides (RiPPs). Lasso peptides act upon several bacterial targets, but none have been reported to inhibit the ribosome, one of the main antibiotic targets in the bacterial cell. Here, we report the identification and characterization of the lasso peptide antibiotic, lariocidin (LAR), and its internally cyclized derivative, lariocidin B (LAR-B), produced by . M2, with broad-spectrum activity against many bacterial pathogens. We show that lariocidins inhibit bacterial growth by binding to the ribosome and interfering with protein synthesis. Structural, genetic, and biochemical data show that lariocidins bind at a unique site in the small ribosomal subunit, where they interact with the 16S rRNA and aminoacyl-tRNA, inhibiting translocation and inducing miscoding. LAR is unaffected by common resistance mechanisms, has a low propensity for generating spontaneous resistance, shows no human cell toxicity, and has potent activity in a mouse model of Acinetobacter infection. Our finding of the first ribosome-targeting lasso peptides uncovers new routes toward discovering alternative protein synthesis inhibitors and offers a new chemical scaffold for developing much-needed antibacterial drugs.

PubMed: 39372947
DOI: 10.21203/rs.3.rs-5058118/v1

実験手法

X-RAY DIFFRACTION (2.5 Å)