A viral block on host protein synthesis As the coronavirus disease 2019 (COVID-19) pandemic continues to cause devastation, scientists race to increase their understanding of the disease-causing severe acute respiratory syndrome coronavirus 2. Once inside host cells, not only does the virus hijack the cells' translational machinery to make viral proteins, but the virulence factor nonstructural protein 1 (Nsp1) also shuts down translation of host messenger RNA. Thoms et al. determined a 2.6-angstrom resolution cryo–electron microscopy structure of a reconstituted complex of Nsp1 bound to the human 40S ribosomal subunit and showed that Nsp1 blocks the messenger RNA entry tunnel. A structural inventory of native Nsp1-ribosome complexes from human cells confirms this mechanism. Cellular studies show that the translational shutdown almost completely inhibits the innate immune response. The binding pocket on the ribosome may be a target for drugs to treat COVID-19. Science, this issue p. 1249 SARS-CoV-2 protein Nsp1 suppresses host translation and immune responses by blocking the ribosomal mRNA entry tunnel. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the current coronavirus disease 2019 (COVID-19) pandemic. A major virulence factor of SARS-CoVs is the nonstructural protein 1 (Nsp1), which suppresses host gene expression by ribosome association. Here, we show that Nsp1 from SARS-CoV-2 binds to the 40S ribosomal subunit, resulting in shutdown of messenger RNA (mRNA) translation both in vitro and in cells. Structural analysis by cryo–electron microscopy of in vitro–reconstituted Nsp1-40S and various native Nsp1-40S and -80S complexes revealed that the Nsp1 C terminus binds to and obstructs the mRNA entry tunnel. Thereby, Nsp1 effectively blocks retinoic acid–inducible gene I–dependent innate immune responses that would otherwise facilitate clearance of the infection. Thus, the structural characterization of the inhibitory mechanism of Nsp1 may aid structure-based drug design against SARS-CoV-2.

中文翻译：

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SARS-CoV-2 的 Nsp1 蛋白翻译关闭和免疫逃避的结构基础


病毒对宿主蛋白质合成的阻断随着 2019 年冠状病毒病 (COVID-19) 大流行继续造成破坏，科学家们竞相加深对引起疾病的严重急性呼吸综合征冠状病毒 2 的了解。一旦进入宿主细胞，不仅病毒劫持细胞的翻译机制来制造病毒蛋白，但毒力因子非结构蛋白 1 (Nsp1) 也会关闭宿主信使 RNA 的翻译。汤姆斯等人。确定了与人 40S 核糖体亚基结合的 Nsp1 重组复合物的 2.6 埃分辨率冷冻电子显微镜结构，并表明 Nsp1 阻断了信使 RNA 进入隧道。来自人类细胞的天然 Nsp1-核糖体复合物的结构清单证实了这一机制。细胞研究表明，翻译关闭几乎完全抑制先天免疫反应。核糖体上的结合口袋可能是治疗 COVID-19 药物的靶点。科学，本期第 14 页。 1249 SARS-CoV-2 蛋白 Nsp1 通过阻断核糖体 mRNA 进入通道来抑制宿主翻译和免疫反应。严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 是当前 2019 年冠状病毒病 (COVID-19) 大流行的病原体。 SARS-CoV 的主要毒力因子是非结构蛋白 1 (Nsp1)，它通过核糖体关联抑制宿主基因表达。在这里，我们证明来自 SARS-CoV-2 的 Nsp1 与 40S 核糖体亚基结合，导致体外和细胞内信使 RNA (mRNA) 翻译的关闭。通过冷冻电子显微镜对体外重建的 Nsp1-40S 以及各种天然 Nsp1-40S 和 -80S 复合物进行的结构分析表明，Nsp1 C 末端结合并阻碍 mRNA 进入通道。 因此，Nsp1 有效阻断视黄酸诱导基因 I 依赖性先天免疫反应，否则会促进感染的清除。因此，Nsp1 抑制机制的结构表征可能有助于针对 SARS-CoV-2 的基于结构的药物设计。