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Structural basis for selective stalling of human ribosome nascent chain complexes by a drug-like molecule

机译：用药物样分子选择性分化人核糖体新链复合物的结构基础

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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 peptidyl-transfer 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.
机译：药物状分子PF-06446846（PF846）结合人核糖体，并选择性地通过未知机制延长少量蛋白的翻译。在PF846停滞的人核糖体的鼻腔组合物的结构中，PF846在由28s核糖体RNA形成的真核特异性袋中结合在核糖体的出口隧道中，并改变新生多肽链的路径。 PF846在旋转的旋转状态下停止平移核糖体，其中肽基转移RNA 3'-CCA末端在肽基转移酶中心中不当地停靠。使用翻译提取物的MRNA库的信使RNA的选择揭示了PF846可以扭转翻译伸长，逮捕终止甚至增强翻译，具体取决于新生链序列上下文。这些结果照亮了小分子如何通过人性核体选择性地靶向翻译，并为开发调节治疗素蛋白的产生的小分子提供基础。

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    Li Wenfei; Ward Fred R.; McClure Kim F.; Chang Stacey Tsai-Lan; Montabana Elizabeth; Liras Spiros; Dullea Robert G.; Cate Jamie H. D.;

  • 作者单位

    Univ Calif Berkeley Dept Mol &

    Cell Biol 229 Stanley Hall Berkeley CA 94720 USA;

    Univ Calif Berkeley Dept Mol &

    Cell Biol 229 Stanley Hall Berkeley CA 94720 USA;

    Pfizer Worldwide Res &

    Dev Pfizer Med Chem Cambridge MA USA;

    Univ Calif Berkeley Dept Mol &

    Cell Biol 229 Stanley Hall Berkeley CA 94720 USA;

    Lawrence Berkeley Natl Lab Mol Biophys &

    Bioimaging Div Berkeley CA 94720 USA;

    Pfizer Worldwide Res &

    Dev Pfizer Med Chem Cambridge MA USA;

    Pfizer Worldwide Res &

    Dev Cardiovasc Metab &

    Endocrine Dis Res Unit Cambridge MA USA;

    Univ Calif Berkeley Dept Mol &

    Cell Biol 229 Stanley Hall Berkeley CA 94720 USA;

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  • 正文语种 eng
  • 中图分类 分子生物学;
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