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

Xuanyu Nan, Yujie Li, Rui Zhang, Ruoke Wang, Niannian Lv, Jiayi Li, Yuanfang Chen, Bini Zhou, Yangjunqi Wang, Ziyi Wang, Jiayi Zhu, Jing Chen, Jinqian Li, Wenlong Chen, Qi Zhang, Xuanling Shi, Changwen Zhao, Chunying Chen, Zhihua Liu, Yuliang Zhao, Dongsheng Liu, Xinquan Wang, Li-Tang Yan, Taisheng Li (), Linqi Zhang () and Yuhe R. Yang ()
Additional contact information
Xuanyu Nan: National Center for Nanoscience and Technology
Yujie Li: Tsinghua University
Rui Zhang: Tsinghua University
Ruoke Wang: Tsinghua University
Niannian Lv: National Center for Nanoscience and Technology
Jiayi Li: National Center for Nanoscience and Technology
Yuanfang Chen: National Center for Nanoscience and Technology
Bini Zhou: Tsinghua University
Yangjunqi Wang: National Center for Nanoscience and Technology
Ziyi Wang: Tsinghua University
Jiayi Zhu: National Center for Nanoscience and Technology
Jing Chen: Tsinghua University
Jinqian Li: Tsinghua University
Wenlong Chen: Tsinghua University
Qi Zhang: Tsinghua University
Xuanling Shi: Tsinghua University
Changwen Zhao: Beijing University of Chemical Technology
Chunying Chen: National Center for Nanoscience and Technology
Zhihua Liu: Chinese Academy of Medical Sciences and Peking Union Medical College
Yuliang Zhao: National Center for Nanoscience and Technology
Dongsheng Liu: Tsinghua University
Xinquan Wang: Tsinghua University
Li-Tang Yan: Tsinghua University
Taisheng Li: Chinese Academy of Medical Science and Peking Union Medical College
Linqi Zhang: Tsinghua University
Yuhe R. Yang: National Center for Nanoscience and Technology

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54746-5

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