SARS-CoV-2 Omicron Variant: ACE2 Binding, Cryo-EM Structure of Spike Protein-ACE2 Complex and Antibody Evasion

  1. Dhiraj Mannar
  2. James W. Saville
  3. Xing Zhu
  4. Shanti S. Srivastava
  5. Alison M. Berezuk
  6. Katharine S. Tuttle
  7. Citlali Marquez
  8. Inna Sekirov
  9. Sriram Subramaniam

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Abstract

The newly reported Omicron variant is poised to replace Delta as the most rapidly spread SARS-CoV-2 variant across the world. Cryo-EM structural analysis of the Omicron variant spike protein in complex with human ACE2 reveals new salt bridges and hydrogen bonds formed by mutated residues R493, S496 and R498 in the RBD with ACE2. These interactions appear to compensate for other Omicron mutations such as K417N known to reduce ACE2 binding affinity, explaining our finding of similar biochemical ACE2 binding affinities for Delta and Omicron variants. Neutralization assays show that pseudoviruses displaying the Omicron spike protein exhibit increased antibody evasion, with greater evasion observed in sera obtained from unvaccinated convalescent patients as compared to doubly vaccinated individuals (8-vs 3-fold). The retention of strong interactions at the ACE2 interface and the increase in antibody evasion are molecular factors that likely contribute to the increased transmissibility of the Omicron variant.

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  1. ScreenIT

    SciScore for 10.1101/2021.12.19.473380: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: Ethics Statement: Patient derived sera samples were collected according to the CARE COVID Study (http://www.bccdc.ca/health-professionals/clinical-resources/covid-19-care/covid-19-serology-care-covid-study) with ethics approval from the UBC Clinical Research Ethics Board.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    Pseudotyped retroviral particles were produced in HEK293T cells as described previously (32).
    HEK293T
    suggested: KCB Cat# KCB 200744YJ, RRID:CVCL_0063)
    For neutralization assays, HEK293T-ACE2-TMPRSS2 cells (33) (BEI Resources cat# NR-55293) were seeded in 384-well plates at 20 000 cells.
    HEK293T-ACE2-TMPRSS2
    suggested: None
    Recombinant DNA
    SentencesResources
    The SARS-CoV-2 Omicron HexaPro S protein gene was synthesized and inserted into pcDNA3.1
    pcDNA3.1
    suggested: RRID:Addgene_79663)
    Software and Algorithms
    SentencesResources
    All data processing was done in cryoSPARC v.
    cryoSPARC
    suggested: (cryoSPARC, RRID:SCR_016501)
    0.9.3 (36), followed by iterative rounds of real-space refinement in COOT and Phenix v.
    COOT
    suggested: (Coot, RRID:SCR_014222)
    Model validation was performed using MolProbity (38).
    MolProbity
    suggested: (MolProbity, RRID:SCR_014226)
    1.1.1 (39), and PyMOL (v.2.2 Schrodinger, LLC).
    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: Please consider improving the rainbow (“jet”) colormap(s) used on pages 18 and 20. 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.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

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  2. Version published to 10.1101/2021.12.19.473380v1 on bioRxiv