7KGB

CryoEM structure of A2296-methylated Mycobacterium tuberculosis ribosome bound with SEQ-9

これはPDB形式変換不可エントリーです。

7KGB の概要

• エントリーDOI: 10.2210/pdb7kgb/pdb
• EMDBエントリー: 22865
• 分子名称: 50S ribosomal protein L32, 50S ribosomal protein L3, 50S ribosomal protein L4, ... (55 entities in total)
• 機能のキーワード: antibiotic, methylation, pathogen, ribosome, ribosome-antibiotic complex, ribosome/antibiotic
• 由来する生物種: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv); 詳細
• タンパク質・核酸の鎖数: 52
• 化学式量合計: 2272100.28

構造登録者

Cui, Z.,Zhang, J. (登録日: 2020-10-16, 公開日: 2022-01-19, 最終更新日: 2024-05-29)

主引用文献

Zhang, J.,Lair, C.,Roubert, C.,Amaning, K.,Barrio, M.B.,Benedetti, Y.,Cui, Z.,Xing, Z.,Li, X.,Franzblau, S.G.,Baurin, N.,Bordon-Pallier, F.,Cantalloube, C.,Sans, S.,Silve, S.,Blanc, I.,Fraisse, L.,Rak, A.,Jenner, L.B.,Yusupova, G.,Yusupov, M.,Zhang, J.,Kaneko, T.,Yang, T.J.,Fotouhi, N.,Nuermberger, E.,Tyagi, S.,Betoudji, F.,Upton, A.,Sacchettini, J.C.,Lagrange, S.
Discovery of natural-product-derived sequanamycins as potent oral anti-tuberculosis agents.
Cell, 2023

PubMed Abstract: The emergence of drug-resistant tuberculosis has created an urgent need for new anti-tubercular agents. Here, we report the discovery of a series of macrolides called sequanamycins with outstanding in vitro and in vivo activity against Mycobacterium tuberculosis (Mtb). Sequanamycins are bacterial ribosome inhibitors that interact with the ribosome in a similar manner to classic macrolides like erythromycin and clarithromycin, but with binding characteristics that allow them to overcome the inherent macrolide resistance of Mtb. Structures of the ribosome with bound inhibitors were used to optimize sequanamycin to produce the advanced lead compound SEQ-9. SEQ-9 was efficacious in mouse models of acute and chronic TB as a single agent, and it demonstrated bactericidal activity in a murine TB infection model in combination with other TB drugs. These results support further investigation of this series as TB clinical candidates, with the potential for use in new regimens against drug-susceptible and drug-resistant TB.

PubMed: 36827973
DOI: 10.1016/j.cell.2023.01.043

実験手法

ELECTRON MICROSCOPY (2.7 Å)