Structural basis for antibody resistance to SARS-CoV-2 omicron variant

  1. Gabriele Cerutti
  2. Yicheng Guo
  3. Lihong Liu
  4. Zhening Zhang
  5. Liyuan Liu
  6. Yang Luo
  7. Yiming Huang
  8. Harris H. Wang
  9. David D. Ho
  10. Zizhang Sheng
  11. Lawrence Shapiro

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Abstract

The recently reported B.1.1.529 Omicron variant of SARS-CoV-2 includes 34 mutations in the spike protein relative to the Wuhan strain that initiated the COVID-19 pandemic, including 15 mutations in the receptor binding domain (RBD). Functional studies have shown omicron to substantially escape the activity of many SARS-CoV-2-neutralizing antibodies. Here we report a 3.1 Å resolution cryo-electron microscopy (cryo-EM) structure of the Omicron spike protein ectodomain. The structure depicts a spike that is exclusively in the 1-RBD-up conformation with increased mobility and inter-protomer asymmetry. Many mutations cause steric clashes and/or altered interactions at antibody binding surfaces, whereas others mediate changes of the spike structure in local regions to interfere with antibody recognition. Overall, the structure of the omicron spike reveals how mutations alter its conformation and explains its extraordinary ability to evade neutralizing antibodies.

Highlights

  • SARS-CoV-2 omicron spike exclusively adopts 1-RBD-up conformation

  • Omicron substitutions alter conformation and mobility of RBD

  • A subset of omicron mutations change the local conformation of spike

  • The structure reveals the basis of antibody neutralization escape

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  1. ScreenIT

    SciScore for 10.1101/2021.12.21.473620: (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
    Motion correction, CTF estimation, particle picking, extraction, 2D classification, ab initio model generation, 3D classification, 3D refinements and local resolution estimation were carried out in cryoSPARC 3.2 (Punjani et al., 2017) The final 3D reconstruction was obtained using non-uniform refinement with C1 symmetry, achieving a resolution of 3.1 Å.
    cryoSPARC
    suggested: (cryoSPARC, RRID:SCR_016501)
    Automated and manual model building were iteratively performed using real space refinement in Phenix (Adams et al., 2010) and Coot (Emsley and Cowtan, 2004) respectively.
    Coot
    suggested: (Coot, RRID:SCR_014222)
    Half maps were provided to Resolve Cryo-EM tool in Phenix to support manual model building (Terwilliger et al., 2020).
    Phenix
    suggested: (Phenix, RRID:SCR_014224)
    Geometry validation and structure quality assessment were performed using EMRinger (Barad et al., 2015) and Molprobity (Davis et al., 2004).
    Molprobity
    suggested: (MolProbity, RRID:SCR_014226)
    Calculation of domain angles and distance and identification of domain interfaces: PyMOL was used to perform the angle and distance calculations and generate plots (Schrodinger, 2015).
    PyMOL
    suggested: (PyMOL, RRID:SCR_000305)
    PISA was used to identify interface residues, as well as calculate buried accessible surface area and identify polar interactions (Winn et al., 2011).
    PISA
    suggested: (PISA, RRID:SCR_015749)

    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 page 23. 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.

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  2. Version published to 10.1101/2021.12.21.473620v1 on bioRxiv