6XA1

Structure of a drug-like compound stalled human translation termination complex

これはPDB形式変換不可エントリーです。

6XA1 の概要

• エントリーDOI: 10.2210/pdb6xa1/pdb
• EMDBエントリー: 22085
• 分子名称: 60S ribosomal protein L8, 60S ribosomal protein L7a, 60S ribosomal protein L9, ... (87 entities in total)
• 機能のキーワード: selectively stalling, translation termination, drug-like compound, human ribosome, ribosome
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 83
• 化学式量合計: 3134503.88

構造登録者

Li, W.,Cate, J. (登録日: 2020-06-03, 公開日: 2020-10-07, 最終更新日: 2024-12-25)

主引用文献

Li, W.,Chang, S.T.,Ward, F.R.,Cate, J.H.D.
Selective inhibition of human translation termination by a drug-like compound.
Nat Commun, 11:4941-4941, 2020

PubMed Abstract: Methods to directly inhibit gene expression using small molecules hold promise for the development of new therapeutics targeting proteins that have evaded previous attempts at drug discovery. Among these, small molecules including the drug-like compound PF-06446846 (PF846) selectively inhibit the synthesis of specific proteins, by stalling translation elongation. These molecules also inhibit translation termination by an unknown mechanism. Using cryo-electron microscopy (cryo-EM) and biochemical approaches, we show that PF846 inhibits translation termination by arresting the nascent chain (NC) in the ribosome exit tunnel. The arrested NC adopts a compact α-helical conformation that induces 28 S rRNA nucleotide rearrangements that suppress the peptidyl transferase center (PTC) catalytic activity stimulated by eukaryotic release factor 1 (eRF1). These data support a mechanism of action for a small molecule targeting translation that suppresses peptidyl-tRNA hydrolysis promoted by eRF1, revealing principles of eukaryotic translation termination and laying the foundation for new therapeutic strategies.

PubMed: 33009412
DOI: 10.1038/s41467-020-18765-2

実験手法

ELECTRON MICROSCOPY (2.8 Å)