Structure, mechanism and crystallographic fragment screening of the SARS-CoV-2 NSP13 helicase

  1. Joseph A. Newman
  2. Alice Douangamath
  3. Setayesh Yadzani
  4. Yuliana Yosaatmadja
  5. Antony Aimon
  6. José Brandão-Neto
  7. Louise Dunnett
  8. Tyler Gorrie-stone
  9. Rachael Skyner
  10. Daren Fearon
  11. Matthieu Schapira
  12. Frank von Delft
  13. Opher Gileadi

Reviewed by

Read the full article

Listed in

Log in to save this article

Abstract

There is currently a lack of effective drugs to treat people infected with SARS-CoV-2, the cause of the global COVID-19 pandemic. The SARS-CoV-2 Non-structural protein 13 (NSP13) has been identified as a target for anti-virals due to its high sequence conservation and essential role in viral replication. Structural analysis reveals two “druggable” pockets on NSP13 that are among the most conserved sites in the entire SARS-CoV-2 proteome. Here we present crystal structures of SARS-CoV-2 NSP13 solved in the APO form and in the presence of both phosphate and a non-hydrolysable ATP analog. Comparisons of these structures reveal details of conformational changes that provide insights into the helicase mechanism and possible modes of inhibition. To identify starting points for drug development we have performed a crystallographic fragment screen against NSP13. The screen reveals 65 fragment hits across 52 datasets opening the way to structure guided development of novel antiviral agents.

Article activity feed

  1. Version published to 10.1038/s41467-021-25166-6
  2. ScreenIT

    SciScore for 10.1101/2021.03.15.435326: (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.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    For overexpression the plasmid was transformed into E. coli BL21 Rosetta2 cells.
    Rosetta2
    suggested: None
    Software and Algorithms
    SentencesResources
    Refinement was performed using PHENIX REFINE(33).
    PHENIX
    suggested: (Phenix, RRID:SCR_014224)
    Refinement was performed using REFMAC(35) or BUSTER.
    BUSTER
    suggested: (BUSTER, RRID:SCR_015653)

    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.
    • No funding statement was detected.
    • 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.

  3. Version published to 10.1101/2021.03.15.435326v1 on bioRxiv