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

By Yan Gao, Liming Yan, Yucen Huang, Fengjiang Liu, Yao Zhao, Lin Cao, Tao Wang, Qianqian Sun, Z. Ming, Lianqi Zhang and 18 more. Science, 2020

1,416 citations recorded by the source corpus.

The COVID-19 RNA-synthesizing machine 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.

Subfields: Cardiology and Cardiovascular Medicine, Infectious Diseases

View Paper: https://www.semanticscholar.org/paper/f593e1eda77495997c0e21deb48656b57099620b

How researchers see this paper

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W. Dejnirattisai
A. Tuekprakhon
J. Huo
Chang Liu
H. Ginn
Daming Zhou
Taj Mohammad
P. Supasa

Citations in the corpus

RCSB Protein Data Bank: powerful new tools for exploring 3D structures of biological macromolecules for basic and applied research and education in fundamental biology, biomedicine, biotechnology, bioengineering and energy sciences (2020, neutral): “6W9C (16)], RNA-dependent RNA polymerase [RdRPNsp7/Nsp82/Nsp12, 6M71 (17)], RNA helicase [∼99% identical SARS-CoV Nsp13, 6JYT (18)], endoribonuclease [Nsp15, 6VWW (19)] and 2′-O-methyltransferase [Nsp16, 6WVN (20)].”
COVID-19: The first documented coronavirus pandemic in history (2020, neutral): “[RdRp]), nsp13 (helicase), and other nsps [10,13,20].”
Insights into SARS-CoV-2 genome, structure, evolution, pathogenesis and therapies: Structural genomics approach (2020, positive): “that remdesivir binds to RdRp and inhibits its activity [75].”
Structure of replicating SARS-CoV-2 polymerase (2020, background): “The structure of the RdRp was recently reported 16 and is highly similar to the RdRp of SARS-CoV 17 , a zoonotic coronavirus that spread into the human population in 2002 1 .”
SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape from neutralizing antibody responses (2022, positive): “The left ﬂank epitope, which is not mutated in Omicron, is used by antibodies that do not block ACE2 binding but are protective (Barnes et al., 2020; Dejnirattisai et al., 2021a; Hastie et al., 2021; Huang et al., 2021; Zhou et al., 2020).”
Structural Basis for RNA Replication by the SARS-CoV-2 Polymerase (2020, neutral): “However, the existing structures of the complexes to date (Gao et al., 2020; Yin et al., 2020) have not revealed the complete nsp8.”