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Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir

Wanchao YinDepartment of Biophysics, and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, ChinaChunyou MaoZhejiang UniversityXiaodong LuanTsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, ChinaDandan ShenZhejiang UniversityQingya ShenDepartment of Biophysics, and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, ChinaHaixia SuThe CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, ChinaXiaoxi WangShanghai Institute of Materia MedicaFulai ZhouShanghai Institute of Materia MedicaWenfeng ZhaoThe CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, ChinaMinqi GaoWuxiBiortus Biosciences Co. Ltd., Jiangyin 214437, ChinaShenghai ChangCenter of Diagnostic Electron Microscopy, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, ChinaYuanchao XieThe CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, ChinaGuanghui TianThe CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, ChinaHe‐wei JiangThe CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, ChinaSheng‐ce TaoShanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, ChinaJingshan ShenThe CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, ChinaYi JiangUniversity of Chinese Academy of SciencesHualiang JiangUniversity of Chinese Academy of Sciences, Beijing 100049, ChinaYechun XuUniversity of Chinese Academy of SciencesShuyang ZhangTsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, ChinaYan ZhangDepartment of Biophysics, and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, ChinaH. Eric XuUniversity of Chinese Academy of Sciences

2020en

ABI

Annotatsiya

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.

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DOI: 10.1126/science.abc1560

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