Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2
Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2
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DOI：
10.1126/science.abc8665
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发表时间：
2020-09-04
期刊：
影响因子：
56.9
通讯作者：
Beckmann, Roland
中科院分区：
文献类型：
--
作者：
Thoms, Matthias;Buschauer, Robert;Beckmann, Roland
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）是当前2019冠状病毒病（COVID-19）大流行的病原体。SARS冠状病毒的一个主要毒力因子是非结构蛋白1（Nsp 1），它通过核糖体结合抑制宿主基因的表达。在这里，我们表明来自SARS-CoV-2的Nsp 1与40 S核糖体亚基结合，导致体外和细胞中信使RNA（mRNA）翻译的停止。通过冷冻电子显微镜对体外重构的Nsp 1 - 40 S和各种天然Nsp 1 - 40 S和-80 S复合物进行的结构分析显示，Nsp 1 C末端结合并阻塞mRNA进入通道。因此，Nsp 1有效地阻断视黄酸诱导的基因I依赖性先天免疫应答，否则将有助于清除感染。因此，Nsp 1抑制机制的结构表征可能有助于基于结构的抗SARS-CoV-2药物设计。
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.