Structure of a SARS-CoV-2 spike S2 subunit in a pre-fusion, open conformation
Open accessPublished version of a preprint
Abstract
The 800 million human infections with SARS-CoV-2 and the likely emergence of new variants and additional coronaviruses necessitate a better understanding of the essential spike glycoprotein and the development of immunogens that foster broader and more durable immunity. The S2 fusion subunit is more conserved in sequence, is essential to function, and would be a desirable immunogen to boost broadly reactive antibodies. It is, however, unstable in structure and in its wild-type form, cannot be expressed alone without irreversible collapse into a six-helix bundle. In addition to the irreversible conformational changes of fusion, biophysical measurements indicate that spike also undergoes a reversible breathing action. However, spike in an open, "breathing" conformation has not yet been visualized at high resolution. Here we describe an S2-only antigen, engineered to remain in its relevant, pre-fusion viral surface conformation in the absence of S1. We also describe a panel of natural human antibodies specific for S2 from vaccinated and convalescent individuals. One of these mAbs, from a convalescent individual, afforded a high-resolution cryo-EM structure of the prefusion S2. The structure reveals a complex captured in an "open" conformation with greater stabilizing intermolecular interactions at the base and a repositioned fusion peptide. Together, this work provides an antigen for advancement of next-generation "booster" immunogens and illuminates the likely breathing adjustments of the coronavirus spike.
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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine
Polack, F. P., Thomas, S. J., Kitchin, N., Absalon, J., Gurtman, A., Lockhart, S., Perez, J. L., Pérez Marc, G., Moreira, E. D., Zerbini, C., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2034577 · Cited by 14,592 · see citing works
Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine
Baden, L. R., El Sahly, H. M., Essink, B., Kotloff, K., Frey, S., Novak, R., Diemert, D., Spector, S. A., Rouphael, N., Creech, C. B., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2035389 · Cited by 10,119 · see citing works
Antibody Recognition of a Highly Conserved Influenza Virus Epitope
Ekiert, D. C., Bhabha, G., Elsliger, M.-A., Friesen, R. H. E., Jongeneelen, M., Throsby, M., Goudsmit, J., & Wilson, I. A. (2009) · Science · doi:10.1126/science.1171491 · Cited by 1,326 · see citing works
Structures and mechanisms of viral membrane fusion proteins: multiple variations on a common theme
White, J. M., Delos, S. E., Brecher, M., & Schornberg, K. (2008) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409230802058320 · Cited by 892 · see citing works
Barnes, C. O., West, A. P., Huey-Tubman, K. E., Hoffmann, M. A. G., Sharaf, N. G., Hoffman, P. R., Koranda, N., Gristick, H. B., Gaebler, C., Muecksch, F., et al. (2020) · Cell · doi:10.1016/j.cell.2020.06.025 · Cited by 795 · see citing works
Wrobel, A. G., Benton, D. J., Xu, P., Roustan, C., Martin, S. R., Rosenthal, P. B., Skehel, J. J., & Gamblin, S. J. (2020) · Nature Structural & Molecular Biology · doi:10.1038/s41594-020-0468-7 · Cited by 544 · see citing works
Maturation and persistence of the anti-SARS-CoV-2 memory B cell response
Sokal, A., Chappert, P., Barba-Spaeth, G., Roeser, A., Fourati, S., Azzaoui, I., Vandenberghe, A., Fernandez, I., Meola, A., Bouvier-Alias, M., et al. (2021) · Cell · doi:10.1016/j.cell.2021.01.050 · Cited by 340 · see citing works
Nguyen-Contant, P., Embong, A. K., Kanagaiah, P., Chaves, F. A., Yang, H., Branche, A. R., Topham, D. J., & Sangster, M. Y. (2020) · mBio · doi:10.1128/mbio.01991-20 · Cited by 204 · see citing works
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- Authors
- Olmedillas, E., Rajamanickam, R. R., Avalos, R. D., Ana-Sosa-Batiz, F., Zyla, D., Zandonatti, M. A., Harkins, S. S., Shresta, S., Hastie, K. M., & Saphire, E. O.
- Affiliations
- La Jolla Institute for Immunology (US)
- Corresponding author
- Hastie, Kathryn M.
- Saphire, Erica Ollmann
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2025-08
- Volume
- 44
- Issue
- 8
- Pages
- 116052
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC10760097
- OpenAlex
- W4412561426
- Cited by
- 19
- References
- 9
- Citations by year
- 2026: 11 · 2025: 5 · 2024: 3
- FWCI
- 12.31
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- Funders
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases Division of Microbiology and Infectious Diseases (NIAID P01 AI165072)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Keywords
- SARS-CoV-2, prefusion conformation, open conformation, fusion peptide, six-helix bundle, respiratory motion, monoclonal antibodies, coronavirus spike protein
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