2. Academic Validation
  3. 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

  • Science. 2020 Jun 26;368(6498):1499-1504. doi: 10.1126/science.abc1560.
Wanchao Yin  # 1 2,  Chunyou Mao  # 2,  Xiaodong Luan  # 3 4 5,  Dan-Dan Shen  # 2,  Qingya Shen  # 2,  Haixia Su  # 1 6,  Xiaoxi Wang 1,  Fulai Zhou 1,  Wenfeng Zhao 1,  Minqi Gao 7,  Shenghai Chang 8 9,  Yuan-Chao Xie 1,  Guanghui Tian 1,  He-Wei Jiang 10,  Sheng-Ce Tao 10,  Jingshan Shen 1 6,  Yi Jiang 1 6,  Hualiang Jiang 1 6,  Yechun Xu 11 6,  Shuyang Zhang 12 5 3,  Yan Zhang 13 14,  H Eric Xu 11 6
Affiliations

Affiliations

  • 1 The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2 Department of Biophysics, and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 3 School of Medicine, Tsinghua University, Haidian District, Beijing 100084, China.
  • 4 Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.
  • 5 Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China.
  • 6 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 7 WuxiBiortus Biosciences Co. Ltd., Jiangyin 214437, China.
  • 8 Center of Cryo-Electron Microscopy, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 9 Center of Diagnostic Electron Microscopy, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 10 Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China.
  • 11 The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. eric.xu@simm.ac.cn zhang_yan@zju.edu.cn shuyangzhang103@nrdrs.org ycxu@simm.ac.cn.
  • 12 Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China. eric.xu@simm.ac.cn zhang_yan@zju.edu.cn shuyangzhang103@nrdrs.org ycxu@simm.ac.cn.
  • 13 Department of Biophysics, and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. eric.xu@simm.ac.cn zhang_yan@zju.edu.cn shuyangzhang103@nrdrs.org ycxu@simm.ac.cn.
  • 14 Key Laboratory of Immunity and Inflammatory Diseases of Zhejiang Province, Hangzhou 310058, China.
  • # Contributed equally.
PMID: 32358203 DOI: 10.1126/science.abc1560
Abstract

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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