8VTY

Crystal structure of the wild-type Thermus thermophilus 70S ribosome in complex with ciprofloxacin and protein Y at 2.60A resolution

これはPDB形式変換不可エントリーです。

8VTY の概要

• エントリーDOI: 10.2210/pdb8vty/pdb
• 分子名称: 23S Ribosomal RNA, 50S ribosomal protein L14, 50S ribosomal protein L15, ... (60 entities in total)
• 機能のキーワード: macrolone; macrolide; fluoroquinolone; erythromycin; ciprofloxacin; antibiotic; 70s ribosome; x-ray structure; inhibition of translation; peptidyl transferase center; nascent peptide exit tunnel; multidrug; resistance; methylation; 23s rrna; a2058; erm, ribosome, ribosome-antibiotic complex, ribosome/antibiotic
• 由来する生物種: Escherichia coli K-12; 詳細
• タンパク質・核酸の鎖数: 106
• 化学式量合計: 4427771.26

構造登録者

Aleksandrova, E.V.,Ma, C.-X.,Klepacki, D.,Alizadeh, F.,Vazquez-Laslop, N.,Liang, J.-H.,Polikanov, Y.S.,Mankin, A.S. (登録日: 2024-01-27, 公開日: 2024-08-07, 最終更新日: 2025-03-19)

主引用文献

Aleksandrova, E.V.,Ma, C.X.,Klepacki, D.,Alizadeh, F.,Vazquez-Laslop, N.,Liang, J.H.,Polikanov, Y.S.,Mankin, A.S.
Macrolones target bacterial ribosomes and DNA gyrase and can evade resistance mechanisms.
Nat.Chem.Biol., 20:1680-1690, 2024

PubMed Abstract: Growing resistance toward ribosome-targeting macrolide antibiotics has limited their clinical utility and urged the search for superior compounds. Macrolones are synthetic macrolide derivatives with a quinolone side chain, structurally similar to DNA topoisomerase-targeting fluoroquinolones. While macrolones show enhanced activity, their modes of action have remained unknown. Here, we present the first structures of ribosome-bound macrolones, showing that the macrolide part occupies the macrolide-binding site in the ribosomal exit tunnel, whereas the quinolone moiety establishes new interactions with the tunnel. Macrolones efficiently inhibit both the ribosome and DNA topoisomerase in vitro. However, in the cell, they target either the ribosome or DNA gyrase or concurrently both of them. In contrast to macrolide or fluoroquinolone antibiotics alone, dual-targeting macrolones are less prone to select resistant bacteria carrying target-site mutations or to activate inducible macrolide resistance genes. Furthermore, because some macrolones engage Erm-modified ribosomes, they retain activity even against strains with constitutive erm resistance genes.

PubMed: 39039256
DOI: 10.1038/s41589-024-01685-3

実験手法

X-RAY DIFFRACTION (2.6 Å)