Selective inhibition of human translation by a drug-like compound that traps terminated protein nascent chain on the ribosome
发布时间：2021-05-24
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- 论文名称：
- Selective inhibition of human translation by a drug-like compound that traps terminated protein nascent chain on the ribosome
- 发表刊物：
- Nature Communications
- 关键字：
- selective stalling, translation, new therapeutic strategies, translation termination
- 摘要：
- 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.
- 第一作者：
- Wenfei Li*
- 通讯作者：
- J. Cate
- 全部作者：
- S. Chang, F. Ward
- 论文类型：
- 期刊论文
- 卷号：
- 11
- 期号：
- 4941
- 是否译文：
- 否
- 发表时间：
- 2020-10
- 收录刊物：
- SCI
- 发布期刊链接：
- https://www.nature.com/articles/s41467-020-18765-2
- 发布时间：
- 2021-05-24
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