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

  1. Wanchao Yin
  2. Chunyou Mao
  3. Xiaodong Luan
  4. Dan-Dan Shen
  5. Qingya Shen
  6. Haixia Su
  7. Xiaoxi Wang
  8. Fulai Zhou
  9. Wenfeng Zhao
  10. Minqi Gao
  11. Shenghai Chang
  12. Yuan-Chao Xie
  13. Guanghui Tian
  14. He-Wei Jiang
  15. Sheng-Ce Tao
  16. Jingshan Shen
  17. Yi Jiang
  18. Hualiang Jiang
  19. Yechun Xu
  20. Shuyang Zhang
  21. Yan Zhang
  22. H. Eric Xu

Reviewed by

Read the full article See related articles

Discuss this preprint

Start a discussion What are Sciety discussions?

Listed in

Log in to save this article

Abstract

The pandemic of Corona Virus Disease 2019 (COVID-19) caused by SARS-CoV-2 has become a global crisis. The replication of SARS-CoV-2 requires the viral RNA-dependent RNA polymerase (RdRp), a direct target of the antiviral drug, Remdesivir. Here we report the structure of the SARS-CoV-2 RdRp either in the apo form or in complex with a 50-base template-primer RNA and Remdesivir at a resolution range of 2.5-2.8 Å. The complex structure reveals that the partial double-stranded RNA template is inserted into the central channel of the RdRp where Remdesivir is incorporated into the first replicated base pair and terminates the chain elongation. Our structures provide critical insights into the working mechanism of viral RNA replication and a rational template for drug design to combat the viral infection.

Article activity feed

  1. ScreenIT

    SciScore for 10.1101/2020.04.08.032763: (What is this?)

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

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Image processing and 3D reconstruction of the template and Remdesivir bound complex: Contrast transfer function parameters for each micrograph were determined by Gctf v1.06(37) and particle selection were performed using auto-picking command in RELION-3.0-beta2(38), yielding 2,438,446 particle projections.
    Gctf
    suggested: (GCTF, RRID:SCR_016500)
    This subset of particle projections was subjected to two rounds of Hetero Refinement and two selected subsets containing 580,293 projections were used to obtain a map with resolution of 2.9 Å in cryoSPARC.
    cryoSPARC
    suggested: (cryoSPARC, RRID:SCR_016501)
    Local resolution was determined using the Bsoft package with half maps as input maps(40).
    Bsoft
    suggested: (Bsoft, RRID:SCR_016503)
    The model statistics was validated using MolProbity.
    MolProbity
    suggested: (MolProbity, RRID:SCR_014226)
    Structural figures were prepared in Chimera and PyMOL (https://pymol.org/2/).
    PyMOL
    suggested: (PyMOL, RRID:SCR_000305)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    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 27 and 21. 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.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2020.04.08.032763 on bioRxiv