Structure of SARS-CoV-2 main protease in the apo state reveals the inactive conformation

  1. Xuelan Zhou
  2. Fangling Zhong
  3. Cheng Lin
  4. Xiaohui Hu
  5. Yan Zhang
  6. Bing Xiong
  7. Xiushan Yin
  8. Jinheng Fu
  9. Wei He
  10. Jingjing Duan
  11. Yang Fu
  12. Huan Zhou
  13. Qisheng Wang
  14. Jian Li
  15. Jin Zhang

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Abstract

M pro is of considerable interest as a drug target in the treatment of COVID-19 since the proteolytic activity of this viral protease is essential for viral replication. Here we report the first insight of the structure M pro for SARS-CoV-2 in the inactive conformation under conditions close to the physiological state (pH 7.5) to an overall resolution of 1.9 Å. The comparisons of M pro in different states reveal that substrate binding site and the active site are more flexible in the inactive conformation than that in the active conformations. Notably, compared with the active conformation of the apo state structure in pH7.6 of SARS, the SARS-CoV-2 apo state is in the inactive conformation under condition close to physiological state (pH7.5). Two water molecules are present in the oxyanion hole in our apo state structure, whereas in the ligand-bound structure, water molecular is absence in the same region. This structure provides novel and important insights that have broad implications for understanding the structural basis underlying enzyme activity, and can facilitate rational, structure-based, approaches for the design of specific SARS-CoV-2 ligands as new therapeutic agents.

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  1. ScreenIT

    SciScore for 10.1101/2020.05.12.092171: (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
    The structures of COVID-2019 main protease 3CL were determined by molecular replacement with PHENIX software.
    PHENIX
    suggested: (Phenix, RRID:SCR_014224)
    The program Coot was used to rebuild the initial model.
    Coot
    suggested: (Coot, RRID:SCR_014222)
    The superimposed data was analyzed with PyMOL software package.
    PyMOL
    suggested: (PyMOL, RRID:SCR_000305)

    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: We did not find any issues relating to colormaps.

    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

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  2. Version published to 10.1101/2020.05.12.092171v1 on bioRxiv