Structure of the RNA-dependent RNA polymerase from COVID-19 virus

• Published in: Science (American Association for the Advancement of Science) Vol. 368; no. 6492; pp. 779 - 782
• Main Authors: Gao, Yan, Yan, Liming, Huang, Yucen, Liu, Fengjiang, Zhao, Yao, Cao, Lin, Wang, Tao, Sun, Qianqian, Ming, Zhenhua, Zhang, Lianqi, Ge, Ji, Zheng, Litao, Zhang, Ying, Wang, Haofeng, Zhu, Yan, Zhu, Chen, Hu, Tianyu, Hua, Tian, Zhang, Bing, Yang, Xiuna, Li, Jun, Yang, Haitao, Liu, Zhijie, Xu, Wenqing, Guddat, Luke W., Wang, Quan, Lou, Zhiyong, Rao, Zihe
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 15.05.2020; American Association for the Advancement of Science
• Subjects: Adenosine Monophosphate - analogs & derivatives; Adenosine Monophosphate - metabolism; Adenosine Monophosphate - pharmacology; Alanine - analogs & derivatives; Alanine - metabolism; Alanine - pharmacology; Antiviral Agents - metabolism; Antiviral Agents - pharmacology; Antiviral drugs; Betacoronavirus - enzymology; Biochem; Catalytic Domain; Chemical synthesis; Cofactors; Comparative analysis; Coronaviridae; Coronavirus RNA-Dependent RNA Polymerase; Coronaviruses; COVID-19; Cryoelectron Microscopy; DNA-directed RNA polymerase; Drug Design; Electron microscopy; Microbio; Microscopy; Models, Molecular; Multiprotein Complexes - chemistry; Multiprotein Complexes - metabolism; Multiprotein Complexes - ultrastructure; Nucleotide analogs; Nucleotides; Pandemics; Protein Conformation, beta-Strand; Protein Domains; Replication; Respiratory diseases; RNA polymerase; RNA viruses; RNA-Dependent RNA Polymerase - antagonists & inhibitors; RNA-Dependent RNA Polymerase - chemistry; RNA-Dependent RNA Polymerase - metabolism; RNA-Dependent RNA Polymerase - ultrastructure; RNA-directed RNA polymerase; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Transcription; Viral diseases; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - chemistry; Viral Nonstructural Proteins - metabolism; Viral Nonstructural Proteins - ultrastructure; Viruses
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.abb7498

Many in the scientific community have mobilized to understand the virus that is causing the global coronavirus disease 2019 (COVID-19) pandemic. Gao et al. focused on a complex that plays a key role in the replication and transcription cycle of the virus. They used cryo–electron microscopy to determine a 2.9-angstrom-resolution structure of the RNA-dependent RNA polymerase nsp12, which catalyzes the synthesis of viral RNA, in complex with two cofactors, nsp7 and nsp8. nsp12 is a target for nucleotide analog antiviral inhibitors such as remdesivir, and the structure may provide a basis for designing new antiviral therapeutics. Science , this issue p. 779 The structure of the COVID-19 virus polymerase essential for viral replication provides a basis for the design of new antiviral drugs. A novel coronavirus [severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2)] outbreak has caused a global coronavirus disease 2019 (COVID-19) pandemic, resulting in tens of thousands of infections and thousands of deaths worldwide. The RNA-dependent RNA polymerase [(RdRp), also named nsp12] is the central component of coronaviral replication and transcription machinery, and it appears to be a primary target for the antiviral drug remdesivir. We report the cryo–electron microscopy structure of COVID-19 virus full-length nsp12 in complex with cofactors nsp7 and nsp8 at 2.9-angstrom resolution. In addition to the conserved architecture of the polymerase core of the viral polymerase family, nsp12 possesses a newly identified β-hairpin domain at its N terminus. A comparative analysis model shows how remdesivir binds to this polymerase. The structure provides a basis for the design of new antiviral therapeutics that target viral RdRp.