A single residue switch mediates the broad neutralization of Rotaviruses

Yang Huang, Feibo Song, Yuanjun Zeng, Hui Sun, Roufang Sheng, Xuechun Wang, Liqin Liu, Guoxing Luo, Yanan Jiang, Yaling Chen, Mengxuan Zhang, Shiyin Zhang, Ying Gu, Hai Yu (), Shaowei Li (), Tingdong Li (), Qingbing Zheng (), Shengxiang Ge (), Jun Zhang and Ningshao Xia ()
Additional contact information
Yang Huang: Xiamen University
Feibo Song: Xiamen University
Yuanjun Zeng: Xiamen University
Hui Sun: Xiamen University
Roufang Sheng: Xiamen University
Xuechun Wang: Xiamen University
Liqin Liu: Xiamen University
Guoxing Luo: Xiamen University
Yanan Jiang: Xiamen University
Yaling Chen: Xiamen University
Mengxuan Zhang: Xiamen University
Shiyin Zhang: Xiamen University
Ying Gu: Xiamen University
Hai Yu: Xiamen University
Shaowei Li: Xiamen University
Tingdong Li: Xiamen University
Qingbing Zheng: Xiamen University
Shengxiang Ge: Xiamen University
Jun Zhang: Xiamen University
Ningshao Xia: Xiamen University

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Broadly neutralizing antibodies (bNAbs) could offer escape-tolerant and lasting protection against viral infections and therefore guide development of broad-spectrum vaccines. The increasing challenge posed by viral evolution and immune evasion intensifies the importance of the discovery of bNAbs and their underlying neutralization mechanism. Here, focusing on the pivotal viral protein VP4 of rotavirus (RV), we identify a potent bNAb, 7H13, exhibiting broad-spectrum neutralization across diverse RV genotypes and demonstrating strong prevention of virus infection in female mice. A combination of time-resolved cryo-electron microscopy (cryo-EM) and in situ cryo-electron tomography (cryo-ET) analysis reveals a counterintuitive dynamic process of virus inactivation, in which 7H13 asymmetrically binds to a conserved epitope in the capsid-proximal aspect of VP4, triggers a conformational switch in a critical residue—F418—thereby disrupts the meta-stable conformation of VP4 essential for normal viral infection. Structure-guided mutagenesis corroborates the essential role of the 7H13 heavy chain I54 in activating F418 switch and destabilizing VP4. These findings define an atypical NAbs’ neutralization mechanism and reveal a potential type of virus vulnerable site for universal vaccine and therapeutics design.

Date: 2025
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DOI: 10.1038/s41467-025-56114-3

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