7TOR

Mammalian 80S ribosome bound with the ALS/FTD-associated dipeptide repeat protein GR20

これはPDB形式変換不可エントリーです。

7TOR の概要

• エントリーDOI: 10.2210/pdb7tor/pdb
• EMDBエントリー: 26036
• 分子名称: 18S rRNA, 60S ribosomal protein L7, eL8, ... (85 entities in total)
• 機能のキーワード: ribosomal binding peptide, als/ftd-associated dipeptide repeat protein, ribosome
• 由来する生物種: Oryctolagus cuniculus (rabbit); 詳細
• タンパク質・核酸の鎖数: 86
• 化学式量合計: 3184552.18

構造登録者

Loveland, A.B.,Svidritskiy, E.,Susorov, D.,Lee, S.,Park, A.,Zvornicanin, S.,Demo, G.,Gao, F.B.,Korostelev, A.A. (登録日: 2022-01-24, 公開日: 2022-05-25, 最終更新日: 2024-11-13)

主引用文献

Loveland, A.B.,Svidritskiy, E.,Susorov, D.,Lee, S.,Park, A.,Zvornicanin, S.,Demo, G.,Gao, F.B.,Korostelev, A.A.
Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM.
Nat Commun, 13:2776-2776, 2022

PubMed Abstract: Toxic dipeptide-repeat (DPR) proteins are produced from expanded GC repeats in the C9ORF72 gene, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two DPR proteins, poly-PR and poly-GR, repress cellular translation but the molecular mechanism remains unknown. Here we show that poly-PR and poly-GR of ≥20 repeats inhibit the ribosome's peptidyl-transferase activity at nanomolar concentrations, comparable to specific translation inhibitors. High-resolution cryogenic electron microscopy (cryo-EM) reveals that poly-PR and poly-GR block the polypeptide tunnel of the ribosome, extending into the peptidyl-transferase center (PTC). Consistent with these findings, the macrolide erythromycin, which binds in the tunnel, competes with poly-PR and restores peptidyl-transferase activity. Our results demonstrate that strong and specific binding of poly-PR and poly-GR in the ribosomal tunnel blocks translation, revealing the structural basis of their toxicity in C9ORF72-ALS/FTD.

PubMed: 35589706
DOI: 10.1038/s41467-022-30418-0

実験手法

ELECTRON MICROSCOPY (2.9 Å)