Structural basis for selective stalling of human ribosome nascent chain complexes by a drug-like molecule
发布时间：2021-05-24
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- 论文名称：
- Structural basis for selective stalling of human ribosome nascent chain complexes by a drug-like molecule
- 发表刊物：
- Nature Structural&molecular biology
- 关键字：
- Ribosome Nascent Chain Complex, Cryo-EM, Translation Elongation, PCSK9
- 摘要：
- The drug-like molecule PF-06446846 (PF846) binds the human ribosome and selectively blocks the translation of a small number
of proteins by an unknown mechanism. In structures of PF846-stalled human ribosome nascent chain complexes, PF846
binds in the ribosome exit tunnel in a eukaryotic-specific pocket formed by 28S ribosomal RNA, and alters the path of the
nascent polypeptide chain. PF846 arrests the translating ribosome in the rotated state of translocation, in which the peptidyltransfer
RNA 3!-CCA end is improperly docked in the peptidyl transferase center. Selections of messenger RNAs from mRNA
libraries using translation extracts reveal that PF846 can stall translation elongation, arrest termination or even enhance translation,
depending on nascent chain sequence context. These results illuminate how a small molecule selectively targets translation
by the human ribosome, and provides a foundation for developing small molecules that modulate the production of proteins
of therapeutic interest.
- 第一作者：
- Wenfei Li*
- 通讯作者：
- J. Cate#
- 全部作者：
- Ward, K. McClure, S. Chang, E. Montabana, S. Liras, R. Dullea
- 卷号：
- 26
- 期号：
- 6
- 页面范围：
- 501-509
- 是否译文：
- 否
- 发表时间：
- 2019-06
- 发布期刊链接：
- https://www.nature.com/articles/s41594-019-0236-8
- 发布时间：
- 2021-05-24
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