8G2C

Crystal structure of the A2503-C2,C8-dimethylated Thermus thermophilus 70S ribosome in complex with tylosin, mRNA, aminoacylated A-site Phe-tRNAphe, aminoacylated P-site fMet-tRNAmet, and deacylated E-site tRNAphe at 2.65A resolution

これはPDB形式変換不可エントリーです。

8G2C の概要

• エントリーDOI: 10.2210/pdb8g2c/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: cfr, methyltransferase, multidrug, antibiotic, resistance, methylation, a2503, 23s rrna, 70s ribosome, inhibition of translation, peptidyl transferase center, nascent peptide exit tunnel, iboxamycin, tylosin, ribosome
• 由来する生物種: Escherichia coli; 詳細
• タンパク質・核酸の鎖数: 112
• 化学式量合計: 4569683.70

構造登録者

Aleksandrova, E.V.,Wu, K.J.Y.,Tresco, B.I.C.,Syroegin, E.A.,Killeavy, E.E.,Balasanyants, S.M.,Svetlov, M.S.,Gregory, S.T.,Atkinson, G.C.,Myers, A.G.,Polikanov, Y.S. (登録日: 2023-02-03, 公開日: 2023-12-27, 最終更新日: 2024-07-10)

主引用文献

Aleksandrova, E.V.,Wu, K.J.Y.,Tresco, B.I.C.,Syroegin, E.A.,Killeavy, E.E.,Balasanyants, S.M.,Svetlov, M.S.,Gregory, S.T.,Atkinson, G.C.,Myers, A.G.,Polikanov, Y.S.
Structural basis of Cfr-mediated antimicrobial resistance and mechanisms to evade it.
Nat.Chem.Biol., 20:867-876, 2024

PubMed Abstract: The bacterial ribosome is an essential drug target as many clinically important antibiotics bind and inhibit its functional centers. The catalytic peptidyl transferase center (PTC) is targeted by the broadest array of inhibitors belonging to several chemical classes. One of the most abundant and clinically prevalent resistance mechanisms to PTC-acting drugs in Gram-positive bacteria is C8-methylation of the universally conserved A2503 nucleobase by Cfr methylase in 23S ribosomal RNA. Despite its clinical importance, a sufficient understanding of the molecular mechanisms underlying Cfr-mediated resistance is currently lacking. Here, we report a set of high-resolution structures of the Cfr-modified 70S ribosome containing aminoacyl- and peptidyl-transfer RNAs. These structures reveal an allosteric rearrangement of nucleotide A2062 upon Cfr-mediated methylation of A2503 that likely contributes to the reduced potency of some PTC inhibitors. Additionally, we provide the structural bases behind two distinct mechanisms of engaging the Cfr-methylated ribosome by the antibiotics iboxamycin and tylosin.

PubMed: 38238495
DOI: 10.1038/s41589-023-01525-w

実験手法

X-RAY DIFFRACTION (2.65 Å)