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Structural basis for the broad and potent cross-reactivity of an N501Y-centric antibody against sarbecoviruses
More than 80% of SARS-CoV-2 variants, including Alpha and Omicron, contain an N501Y mutation in the receptor-binding domain (RBD) of the spike protein. The N501Y change is an adaptive mutation enabling tighter interaction with the human ACE2 receptor. We have developed a broadly neutralizing antibod...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9714666/ https://www.ncbi.nlm.nih.gov/pubmed/36466915 http://dx.doi.org/10.3389/fimmu.2022.1049867 |
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author | Jeong, Bo-Seong Jeon, Joon Young Lai, Chih-Jen Yun, Hye-Yeoung Jung, Jae U. Oh, Byung-Ha |
author_facet | Jeong, Bo-Seong Jeon, Joon Young Lai, Chih-Jen Yun, Hye-Yeoung Jung, Jae U. Oh, Byung-Ha |
author_sort | Jeong, Bo-Seong |
collection | PubMed |
description | More than 80% of SARS-CoV-2 variants, including Alpha and Omicron, contain an N501Y mutation in the receptor-binding domain (RBD) of the spike protein. The N501Y change is an adaptive mutation enabling tighter interaction with the human ACE2 receptor. We have developed a broadly neutralizing antibody (nAb), D27LEY, whose binding affinity was intentionally optimized for Y501. This N501Y-centric antibody not only interacts with the Y501-containing RBDs of SARS-CoV-2 variants, including Omicron, with pico- or subnanomolar binding affinity, but also binds tightly to the RBDs with a different amino acid at residue 501. The crystal structure of the Fab fragment of D27LEY bound to the RBD of the Alpha variant reveals that the Y501-containing loop adopts a ribbon-like topology and serves as a small but major epitope in which Y501 is a part of extensive intermolecular interactions. A hydrophobic cleft on the most conserved surface of the RBD core serves as another major binding epitope. These data explain the broad and potent cross-reactivity of this N501Y-centric antibody, and suggest that a vaccine antigenic component composed of the RBD core and a part of receptor-binding motif (RBM) containing tyrosine at residue 501 might elicit broad and potent humoral responses across sarbecoviruses. |
format | Online Article Text |
id | pubmed-9714666 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-97146662022-12-02 Structural basis for the broad and potent cross-reactivity of an N501Y-centric antibody against sarbecoviruses Jeong, Bo-Seong Jeon, Joon Young Lai, Chih-Jen Yun, Hye-Yeoung Jung, Jae U. Oh, Byung-Ha Front Immunol Immunology More than 80% of SARS-CoV-2 variants, including Alpha and Omicron, contain an N501Y mutation in the receptor-binding domain (RBD) of the spike protein. The N501Y change is an adaptive mutation enabling tighter interaction with the human ACE2 receptor. We have developed a broadly neutralizing antibody (nAb), D27LEY, whose binding affinity was intentionally optimized for Y501. This N501Y-centric antibody not only interacts with the Y501-containing RBDs of SARS-CoV-2 variants, including Omicron, with pico- or subnanomolar binding affinity, but also binds tightly to the RBDs with a different amino acid at residue 501. The crystal structure of the Fab fragment of D27LEY bound to the RBD of the Alpha variant reveals that the Y501-containing loop adopts a ribbon-like topology and serves as a small but major epitope in which Y501 is a part of extensive intermolecular interactions. A hydrophobic cleft on the most conserved surface of the RBD core serves as another major binding epitope. These data explain the broad and potent cross-reactivity of this N501Y-centric antibody, and suggest that a vaccine antigenic component composed of the RBD core and a part of receptor-binding motif (RBM) containing tyrosine at residue 501 might elicit broad and potent humoral responses across sarbecoviruses. Frontiers Media S.A. 2022-11-17 /pmc/articles/PMC9714666/ /pubmed/36466915 http://dx.doi.org/10.3389/fimmu.2022.1049867 Text en Copyright © 2022 Jeong, Jeon, Lai, Yun, Jung and Oh https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Jeong, Bo-Seong Jeon, Joon Young Lai, Chih-Jen Yun, Hye-Yeoung Jung, Jae U. Oh, Byung-Ha Structural basis for the broad and potent cross-reactivity of an N501Y-centric antibody against sarbecoviruses |
title | Structural basis for the broad and potent cross-reactivity of an N501Y-centric antibody against sarbecoviruses |
title_full | Structural basis for the broad and potent cross-reactivity of an N501Y-centric antibody against sarbecoviruses |
title_fullStr | Structural basis for the broad and potent cross-reactivity of an N501Y-centric antibody against sarbecoviruses |
title_full_unstemmed | Structural basis for the broad and potent cross-reactivity of an N501Y-centric antibody against sarbecoviruses |
title_short | Structural basis for the broad and potent cross-reactivity of an N501Y-centric antibody against sarbecoviruses |
title_sort | structural basis for the broad and potent cross-reactivity of an n501y-centric antibody against sarbecoviruses |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9714666/ https://www.ncbi.nlm.nih.gov/pubmed/36466915 http://dx.doi.org/10.3389/fimmu.2022.1049867 |
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