A thermostable, closed SARS-CoV-2 spike protein trimer
Open accessPublished version of a preprint
Abstract
The spike (S) protein of SARS-CoV-2 mediates receptor binding and cell entry and is the dominant target of the immune system. It exhibits substantial conformational flexibility. It transitions from closed to open conformations to expose its receptor-binding site and, subsequently, from prefusion to postfusion conformations to mediate fusion of viral and cellular membranes. S-protein derivatives are components of vaccine candidates and diagnostic assays, as well as tools for research into the biology and immunology of SARS-CoV-2. Here we have designed mutations in S that allow the production of thermostable, disulfide-bonded S-protein trimers that are trapped in the closed, prefusion state. Structures of the disulfide-stabilized and non-disulfide-stabilized proteins reveal distinct closed and locked conformations of the S trimer. We demonstrate that the designed, thermostable, closed S trimer can be used in serological assays. This protein has potential applications as a reagent for serology, virology and as an immunogen.
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Mutations at K417 are reported to escape neutralization from mAbs, including the recently approved mAb LY-CoV016.
“Importantly, mutations at K417 are reported to escape neutralization from mAbs, including the recently approved mAb LY-CoV016 22,25.”
From Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies (2021) · cites this paper as [25]
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References 53 · Cited by 313
Research works printed but not linked: 1
- [3]Gorbalenya AE The species and its viruses – a statement of the Coronavirus Study Group Biorxiv 2020 10.1101/2020.02.07.937862 · DOI
- Authors
- Xiong, X., Qu, K., Ciazynska, K. A., Hosmillo, M., Carter, A. P., Ebrahimi, S., Ke, Z., Scheres, S. H. W., Bergamaschi, L., Grice, G. L., Zhang, Y., The CITIID-NIHR COVID-19 BioResource Collaboration, Bradley, J., Lyons, P. A., Smith, K. G. C., Toshner, M., Elmer, A., Ribeiro, C., Kourampa, J., Jose, S., Kennet, J., Rowlands, J., Meadows, A., O’Brien, C., Rastall, R., Crucusio, C., Hewitt, S., Price, J., Calder, J., Canna, L., Bucke, A., Tordesillas, H., Harris, J., Ruffolo, V., Domingo, J., Graves, B., Butcher, H., Caputo, D., Le Gresley, E., Dunmore, B. J., Martin, J., Legchenko, E., Treacy, C., Huang, C., Wood, J., Sutcliffe, R., Hodgson, J., Shih, J., Graf, S., Tong, Z., Mescia, F., Tilly, T., O’Donnell, C., Hunter, K., Pointon, L., Pond, N., Wylot, M., Jones, E., Fawke, S., Bullman, B., Bergamaschi, L., Turner, L., Jarvis, I., Omarjee, O., De Sa, A., Marsden, J., Betancourt, A., Perera, M., Epping, M., Richoz, N., Bower, G., Sharma, R., Nice, F., Huhn, O., Stark, H., Walker, N., Stirrups, K., Ovington, N., Dewhust, E., Li, E., Papadia, S., Nathan, J. A., Baker, S., James, L. C., Baxendale, H. E., Goodfellow, I., Doffinger, R., & Briggs, J. A. G.
- Affiliations
- MRC Laboratory of Molecular Biology (GB)
- University of Cambridge (GB)
- Addenbrooke's Hospital (GB)
- Sun Yat-sen University (CN)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- NIHR Cambridge Biomedical Research Centre (GB)
- Papworth Hospital NHS Foundation Trust (GB)
- Corresponding author
- Xiong, Xiaoli
- Briggs, John A. G.
- ORCID
- Xiong, Xiaoli
- Qu, Kun
- Ciazynska, Katarzyna A.
- Hosmillo, Myra
- Carter, Andrew P.
- Ke, Zunlong
- Scheres, Sjors H. W.
- Zhang, Ying
- Bradley, John
- Lyons, Paul A.
- Smith, Kenneth G. C.
- Toshner, Mark
- Kennet, Jane
- Rowlands, Jane
- Price, Jane
- Domingo, Jason
- Dunmore, Benjamin J.
- Martin, Jennifer
- Legchenko, Ekaterina
- Wood, Jennifer
- Mescia, Federica
- Tilly, Tobias
- Pointon, Linda
- Fawke, Stuart
- Omarjee, Ommar
- Perera, Marianne
- Richoz, Nathan
- Sharma, Rahul
- Nice, Francesca
- Stark, Hannah
- Walker, Neil
- Stirrups, Kathy
- Papadia, Sofia
- Nathan, James A.
- Baker, Stephen
- James, Leo C.
- Baxendale, Helen E.
- Goodfellow, Ian
- Doffinger, Rainer
- Briggs, John A. G.
- Venue
- Nature Structural & Molecular Biology
- Published
- 2020-07-31
- Volume
- 27
- Issue
- 10
- Pages
- 934-941
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC7116388
- OpenAlex
- W3046414208
- Cited by
- 313
- References
- 53
- Citations by year
- 2026: 16 · 2025: 30 · 2024: 34 · 2023: 49 · 2022: 72 · 2021: 83 · 2020: 27
- FWCI
- 7.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- National University of Singapore (submittedVersion)
- Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion)
- Griffith Research Online (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- Wellcome Trust (215477/Z/19/Z, Z/17/Z, 206298/B/17/Z, 207498, 207498/Z/17/Z, 210711/Z/18/Z)
- National Institute for Health and Care Research (207498, COVID-19)
- European Commission (HORIZON2020, COVID-19, ERC-CoG-648432)
- Sun Yat-sen University
- Medical Research Council (MC_UP_A025_1013, MC_U105181010, MC_UP_A025_1011, COVID-19, MC_UP_1201/16, 207498/Z/17/Z)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 detection and testing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- SARS-CoV-2 spike protein, spike trimer, closed conformation, disulfide bonds, thermal stability, receptor binding domain, protein engineering, serological assays, immunogen, protein structure
- MeSH terms
- Betacoronavirus, SARS-CoV-2, COVID-19 Testing, Disulfides, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Humans, Immunoglobulin G, Models, Molecular, Mutation, Protein Conformation, Temperature, Protein Engineering, Coronavirus Infections, Clinical Laboratory Techniques, Cryoelectron Microscopy, Protein Multimerization, Protein Stability, Spike Glycoprotein, Coronavirus
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