Exploring distinct modes of inter-spike cross-linking for enhanced neutralization by SARS-CoV-2 antibodies

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its Omicron subvariants drastically amplifies transmissibility, infectivity, and immune escape, mainly due to their resistance to most neutralizing antibodies. Thus, exploring the mechanisms underlying antibody evasion is crucial. Although the full-length native form of antibody, immunoglobulin G (IgG), offers valuable insights into the neutralization, structural investigations primarily focus on the fragment of antigen-binding (Fab). Here, we employ single-particle cryo-electron microscopy (cryo-EM) to characterize a W328-6H2 antibody, in its native IgG form complexed with severe acute respiratory syndrome (SARS), severe acute respiratory syndrome coronavirus 2 wild-type (WT) and Omicron variant BA.1 spike protein (S). Three high-resolution structures reveal that the full-length IgG forms a centered head-to-head dimer of trimer when binds fully stoichiometrically with both SARS and WT S, while adopting a distinct offset configuration with Omicron BA.1 S. Combined with functional assays, our results suggest that, beyond the binding affinity between the RBD epitope and Fab, the higher-order architectures of S trimer and full-length IgG play an additional role in neutralization, enriching our understanding of enhanced neutralization by SARS-CoV-2 antibodies.

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Publication Details

Journal
Nature Communications
Published
2024-12-04
DOI
https://doi.org/10.1038/s41467-024-54746-5
Citations
10
Primary Topic
SARS-CoV-2 and COVID-19 Research
Type
article
Field-Weighted Citation Impact
3.89

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Exploring distinct modes of inter-spike cross-linking for enhanced neutralization by SARS-CoV-2 antibodies

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Nature Communications
SARS-CoV-2 and COVID-19 Research
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article

Exploring distinct modes of inter-spike cross-linking for enhanced neutralization by SARS-CoV-2 antibodies

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article en
10 citations

Abstract

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its Omicron subvariants drastically amplifies transmissibility, infectivity, and immune escape, mainly due to their resistance to most neutralizing antibodies. Thus, exploring the mechanisms underlying antibody evasion is crucial. Although the full-length native form of antibody, immunoglobulin G (IgG), offers valuable insights into the neutralization, structural investigations primarily focus on the fragment of antigen-binding (Fab). Here, we employ single-particle cryo-electron microscopy (cryo-EM) to characterize a W328-6H2 antibody, in its native IgG form complexed with severe acute respiratory syndrome (SARS), severe acute respiratory syndrome coronavirus 2 wild-type (WT) and Omicron variant BA.1 spike protein (S). Three high-resolution structures reveal that the full-length IgG forms a centered head-to-head dimer of trimer when binds fully stoichiometrically with both SARS and WT S, while adopting a distinct offset configuration with Omicron BA.1 S. Combined with functional assays, our results suggest that, beyond the binding affinity between the RBD epitope and Fab, the higher-order architectures of S trimer and full-length IgG play an additional role in neutralization, enriching our understanding of enhanced neutralization by SARS-CoV-2 antibodies.

Nature CommunicationsVol. 15(1)
Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Peking Union Medical College Hospital (CN), Shenzhen Bay Laboratory (CN), Tsinghua–Berkeley Shenzhen Institute (CN), National Center for Nanoscience and Technology (CN), State Key Laboratory of Chemical Engineering (CN), Center for Life Sciences (CN), University of Chinese Academy of Sciences (CN), Beijing University of Chemical Technology (CN), Tsinghua University (CN)
National Natural Science Foundation of China, Chinese Academy of Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Peking Union Medical College, Bijzonder Onderzoeksfonds UGent
Openalex Percentile: Top 6%
SARS-CoV-2 and COVID-19 Research
3.89
DOIOpen Access PDFOpenAlex
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