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

• Published in: Science (American Association for the Advancement of Science) Vol. 368; no. 6498; pp. 1499 - 1504
• Main Authors: Yin, Wanchao, Mao, Chunyou, Luan, Xiaodong, Shen, Dan-Dan, Shen, Qingya, Su, Haixia, Wang, Xiaoxi, Zhou, Fulai, Zhao, Wenfeng, Gao, Minqi, Chang, Shenghai, Xie, Yuan-Chao, Tian, Guanghui, Jiang, He-Wei, Tao, Sheng-Ce, Shen, Jingshan, Jiang, Yi, Jiang, Hualiang, Xu, Yechun, Zhang, Shuyang, Zhang, Yan, Xu, H Eric
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 26-06-2020; American Association for the Advancement of Science
• Subjects: Adenosine Monophosphate - analogs & derivatives; Adenosine Monophosphate - chemistry; Adenosine Monophosphate - metabolism; Adenosine Monophosphate - pharmacology; Alanine - analogs & derivatives; Alanine - chemistry; Alanine - metabolism; Alanine - pharmacology; Antiviral Agents - chemistry; Antiviral Agents - metabolism; Antiviral Agents - pharmacology; Antiviral drugs; Betacoronavirus - drug effects; Betacoronavirus - enzymology; Betacoronavirus - physiology; Biochem; Catalytic Domain; Coronaviridae; Coronavirus RNA-Dependent RNA Polymerase; Coronaviruses; COVID-19; Cryoelectron Microscopy; DNA-directed RNA polymerase; Double-stranded RNA; Drug development; Electron microscopy; Elongated structure; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Models, Molecular; Multiprotein Complexes - chemistry; Nucleotides; Pandemics; Protein Conformation; Replication; Respiratory diseases; RNA polymerase; RNA, Viral - chemistry; RNA, Viral - metabolism; RNA-Dependent RNA Polymerase - antagonists & inhibitors; RNA-Dependent RNA Polymerase - chemistry; RNA-Dependent RNA Polymerase - metabolism; RNA-directed RNA polymerase; SARS-CoV-2; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Transcription; Viral diseases; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - chemistry; Viral Nonstructural Proteins - metabolism; Virus Replication; Viruses
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.abc1560

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.