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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...

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Autores principales: Jeong, Bo-Seong, Jeon, Joon Young, Lai, Chih-Jen, Yun, Hye-Yeoung, Jung, Jae U., Oh, Byung-Ha
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
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.
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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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