Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir
Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir
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DOI：
10.1126/science.abc1560
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发表时间：
2020-06-26
期刊：
影响因子：
56.9
通讯作者：
Xu, H. Eric
中科院分区：
文献类型：
--
作者：
Yin, Wanchao;Mao, Chunyou;Xu, H. Eric
由严重急性呼吸道综合征冠状病毒2型（SARS-CoV-2）引起的2019冠状病毒病（COVID-19）大流行已成为全球危机。SARS-CoV-2的复制需要病毒RNA依赖性RNA聚合酶（RdRp），这是抗病毒药物remdesivir的靶点。在这里，我们报告了SARS-CoV-2 RdRp的冷冻电子显微镜结构，无论是在2.8埃分辨率的apo形式，还是在2.5埃分辨率的50个碱基的模板引物RNA和remdesivir的复合物中。复合物结构揭示了部分双链RNA模板插入RdRp的中央通道，其中remdesivir在第一个复制的碱基对处共价结合到引物链中，并终止链延伸。我们的结构提供了深入了解病毒RNA复制的机制，并为药物设计提供了合理的模板，以对抗病毒感染。
The pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global crisis. Replication of SARS-CoV-2 requires the viral RNA-dependent RNA polymerase (RdRp) enzyme, a target of the antiviral drug remdesivir. Here we report the cryo-electron microscopy structure of the SARS-CoV-2 RdRp, both in the apo form at 2.8-angstrom resolution and in complex with a 50-base template-primer RNA and remdesivir at 2.5-angstrom resolution. The complex structure reveals that the partial double-stranded RNA template is inserted into the central channel of the RdRp, where remdesivir is covalently incorporated into the primer strand at the first replicated base pair, and terminates chain elongation. Our structures provide insights into the mechanism of viral RNA replication and a rational template for drug design to combat the viral infection.