Structure of RNA-dependent RNA polymerase from 2019-nCoV, a major antiviral drug target

  1. Yan Gao
  2. Liming Yan
  3. Yucen Huang
  4. Fengjiang Liu
  5. Yao Zhao
  6. Lin Cao
  7. Tao Wang
  8. Qianqian Sun
  9. Zhenhua Ming
  10. Lianqi Zhang
  11. Ji Ge
  12. Litao Zheng
  13. Ying Zhang
  14. Haofeng Wang
  15. Yan Zhu
  16. Chen Zhu
  17. Tianyu Hu
  18. Tian Hua
  19. Bing Zhang
  20. Xiuna Yang
  21. Jun Li
  22. Haitao Yang
  23. Zhijie Liu
  24. Wenqing Xu
  25. Luke W. Guddat
  26. Quan Wang
  27. Zhiyong Lou
  28. Zihe Rao

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Abstract

A novel coronavirus (2019-nCoV) outbreak has caused a global pandemic resulting in tens of thousands of infections and thousands of deaths worldwide. The RNA-dependent RNA polymerase (RdRp, also named nsp12), which catalyzes the synthesis of viral RNA, is a key component of coronaviral replication/transcription machinery and appears to be a primary target for the antiviral drug, remdesivir. Here we report the cryo-EM structure of 2019-nCoV full-length nsp12 in complex with cofactors nsp7 and nsp8 at a resolution of 2.9-Å. Additional to the conserved architecture of the polymerase core of the viral polymerase family and a nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain featured in coronaviral RdRp, nsp12 possesses a newly identified β-hairpin domain at its N-terminal. Key residues for viral replication and transcription are observed. A comparative analysis to show how remdesivir binds to this polymerase is also provided. This structure provides insight into the central component of coronaviral replication/transcription machinery and sheds light on the design of new antiviral therapeutics targeting viral RdRp.

One Sentence Summary

Structure of 2019-nCov RNA polymerase.

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    SciScore for 10.1101/2020.03.16.993386: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Materials and Methods Figures S1-S7 Tables S1 References (21–28) Materials and Methods:
    Methods
    suggested: None

    Results from OddPub: Thank you for sharing your data.

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on pages 16 and 17. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

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  2. Version published to 10.1101/2020.03.16.993386v2 on bioRxiv
  3. Version published to 10.1101/2020.03.16.993386v1 on bioRxiv