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Potent SARS-CoV-2 neutralizing antibodies directed against spike N-terminal domain target a single supersite
Open accessPublished version of a preprint
Abstract
Numerous antibodies that neutralize SARS-CoV-2 have been identified, and these generally target either the receptor-binding domain (RBD) or the N-terminal domain (NTD) of the viral spike. While RBD-directed antibodies have been extensively studied, far less is known about NTD-directed antibodies. Here, we report cryo-EM and crystal structures for seven potent NTD-directed neutralizing antibodies in complex with spike or isolated NTD. These structures defined several antibody classes, with at least one observed in multiple convalescent donors. The structures revealed that all seven antibodies target a common surface, bordered by glycans N17, N74, N122, and N149. This site-formed primarily by a mobile β-hairpin and several flexible loops-was highly electropositive, located at the periphery of the spike, and the largest glycan-free surface of NTD facing away from the viral membrane. Thus, in contrast to neutralizing RBD-directed antibodies that recognize multiple non-overlapping epitopes, potent NTD-directed neutralizing antibodies appear to target a single supersite.
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“Neutralizing mAbs that bind regions of the viral spike have also been identified (24, 33, 38–42).”
From mRNA vaccination boosts cross-variant neutralizing antibodies elicited by SARS-CoV-2 infection (2021) · cites this paper as [40]
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“that would be predicted to disrupt the so-called “super site” on the NTD mediating neutralization (Cerutti et al., 2021; Figure S2)”
From Reduced neutralization of SARS-CoV-2 B.1.617 by vaccine and convalescent serum (2021) · cites this paper as Cerutti et al., 2021
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Metadata
- Authors
- Cerutti, G., Guo, Y., Zhou, T., Gorman, J., Lee, M., Rapp, M., Reddem, E. R., Yu, J., Bahna, F., Bimela, J., Huang, Y., Katsamba, P. S., Liu, L., Nair, M. S., Rawi, R., Olia, A. S., Wang, P., Zhang, B., Chuang, G.-Y., Ho, D. D., Sheng, Z., Kwong, P. D., & Shapiro, L.
- Affiliations
- Mortimer B. Zuckerman Mind Brain Behavior Institute (US)
- National Institutes of Health (US)
- Aaron Diamond AIDS Research Center (US)
- Corresponding author
- Kwong, Peter D.
- Shapiro, Lawrence
- ORCID
- Venue
- Cell Host & Microbe
- Publisher
- Elsevier BV
- Published
- 2021-05
- Volume
- 29
- Issue
- 5
- Pages
- 819-833.e7
- ISSN
- 1931-3128 (ISSN-L)
- PMC
- PMC7953435
- OpenAlex
- W3136437538
- Cited by
- 519
- References
- 89
- Citations by year
- 2026: 28 · 2025: 39 · 2024: 67 · 2023: 93 · 2022: 141 · 2021: 151
- FWCI
- 35.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Host & Microbe (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Simons Foundation (SF349247)
- National Institute of General Medical Sciences (GM103310, GM129539)
- National Institutes of Health (P41 GM103403, P30 GM124165)
- Vaccine Research Center
- Office of Science (W-31-109-Eng-38)
- Empire State Development's Division of Science, Technology and Innovation
- Basic Energy Sciences
- U.S. Department of Energy
- National Institute of Allergy and Infectious Diseases
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
- Keywords
- SARS-CoV-2, neutralizing antibodies, antibody-antigen complex structure, cryo-EM structure, crystal structure, glycans, beta-hairpin, epitope mapping, convalescent donors, receptor binding domain
- MeSH terms
- Protein Domains, SARS-CoV-2, Antibodies, Viral, Humans, Mutation, Protein Conformation, Antibodies, Neutralizing, Spike Glycoprotein, Coronavirus
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