Structural Basis for Inhibition of the RNA-dependent RNA Polymerase from SARS-CoV-2 by Remdesivir

Overview

Journal Science

Specialty Science

Date 2020 May 3

PMID 32358203

Citations 612

Authors

Wanchao Yin

Chunyou Mao

Xiaodong Luan

Dan-Dan Shen

Qingya Shen

Haixia Su

Xiaoxi Wang

Fulai Zhou

WenFeng Zhao

Minqi Gao

Shenghai Chang

Yuan-Chao Xie

Guanghui Tian

He-Wei Jiang

Sheng-Ce Tao

Jingshan Shen

Yi Jiang

Hualiang Jiang

Yechun Xu

Shuyang Zhang

Yan Zhang

H Eric Xu

Affiliations

Soon will be listed here.

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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References

Peti W, Johnson M, Herrmann T, Neuman B, Buchmeier M, Nelson M . Structural genomics of the severe acute respiratory syndrome coronavirus: nuclear magnetic resonance structure of the protein nsP7. J Virol. 2005; 79(20):12905-13. PMC: 1235862. DOI: 10.1128/JVI.79.20.12905-12913.2005. View

Ahn D, Choi J, Taylor D, Oh J . Biochemical characterization of a recombinant SARS coronavirus nsp12 RNA-dependent RNA polymerase capable of copying viral RNA templates. Arch Virol. 2012; 157(11):2095-104. PMC: 7086750. DOI: 10.1007/s00705-012-1404-x. View

Zhai Y, Sun F, Li X, Pang H, Xu X, Bartlam M . Insights into SARS-CoV transcription and replication from the structure of the nsp7-nsp8 hexadecamer. Nat Struct Mol Biol. 2005; 12(11):980-6. PMC: 7096913. DOI: 10.1038/nsmb999. View

. The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol. 2020; 5(4):536-544. PMC: 7095448. DOI: 10.1038/s41564-020-0695-z. View

Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q . Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science. 2020; 367(6485):1444-1448. PMC: 7164635. DOI: 10.1126/science.abb2762. View

Venkataraman S, Prasad B, Selvarajan R . RNA Dependent RNA Polymerases: Insights from Structure, Function and Evolution. Viruses. 2018; 10(2). PMC: 5850383. DOI: 10.3390/v10020076. View

McDonald S . RNA synthetic mechanisms employed by diverse families of RNA viruses. Wiley Interdiscip Rev RNA. 2013; 4(4):351-67. PMC: 7169773. DOI: 10.1002/wrna.1164. View

Zheng S, Palovcak E, Armache J, Verba K, Cheng Y, Agard D . MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy. Nat Methods. 2017; 14(4):331-332. PMC: 5494038. DOI: 10.1038/nmeth.4193. View

Te Velthuis A, Arnold J, Cameron C, van den Worm S, Snijder E . The RNA polymerase activity of SARS-coronavirus nsp12 is primer dependent. Nucleic Acids Res. 2009; 38(1):203-14. PMC: 2800238. DOI: 10.1093/nar/gkp904. View

10.

Zhou P, Yang X, Wang X, Hu B, Zhang L, Zhang W . A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020; 579(7798):270-273. PMC: 7095418. DOI: 10.1038/s41586-020-2012-7. View

11.

Wrapp D, Wang N, Corbett K, Goldsmith J, Hsieh C, Abiona O . Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020; 367(6483):1260-1263. PMC: 7164637. DOI: 10.1126/science.abb2507. View

12.

Soon F, Suino-Powell K, Li J, Yong E, Xu H, Melcher K . Abscisic acid signaling: thermal stability shift assays as tool to analyze hormone perception and signal transduction. PLoS One. 2012; 7(10):e47857. PMC: 3480437. DOI: 10.1371/journal.pone.0047857. View

13.

Adams P, Afonine P, Bunkoczi G, Chen V, Echols N, Headd J . The Phenix software for automated determination of macromolecular structures. Methods. 2011; 55(1):94-106. PMC: 3193589. DOI: 10.1016/j.ymeth.2011.07.005. View

14.

Pettersen E, Goddard T, Huang C, Couch G, Greenblatt D, Meng E . UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem. 2004; 25(13):1605-12. DOI: 10.1002/jcc.20084. View

15.

Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M . Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020; 30(3):269-271. PMC: 7054408. DOI: 10.1038/s41422-020-0282-0. View

16.

Zhang K . Gctf: Real-time CTF determination and correction. J Struct Biol. 2015; 193(1):1-12. PMC: 4711343. DOI: 10.1016/j.jsb.2015.11.003. View

17.

Punjani A, Rubinstein J, Fleet D, Brubaker M . cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination. Nat Methods. 2017; 14(3):290-296. DOI: 10.1038/nmeth.4169. View

18.

Walls A, Park Y, Tortorici M, Wall A, McGuire A, Veesler D . Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell. 2020; 181(2):281-292.e6. PMC: 7102599. DOI: 10.1016/j.cell.2020.02.058. View

19.

Harder E, Damm W, Maple J, Wu C, Reboul M, Xiang J . OPLS3: A Force Field Providing Broad Coverage of Drug-like Small Molecules and Proteins. J Chem Theory Comput. 2015; 12(1):281-96. DOI: 10.1021/acs.jctc.5b00864. View

20.

Siegel D, Hui H, Doerffler E, Clarke M, Chun K, Zhang L . Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-f][triazin-4-amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses. J Med Chem. 2017; 60(5):1648-1661. DOI: 10.1021/acs.jmedchem.6b01594. View