Authors

Xiaohua Ye, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
Chen Fan, Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences Chinese Academy of Sciences, State Key Laboratory of Molecular Biology, Shanghai, China
Zhiqiang Ku, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
Teng Zuo, Tsinghua University, School of Medicine, Beijing, China
Liangliang Kong, Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences Chinese Academy of Sciences, State Key Laboratory of Molecular Biology, Shanghai, China
Chao Zhang, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Key Laboratory of Molecular Virology and Immunology, Shanghai, China
Jinping Shi, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Key Laboratory of Molecular Virology and Immunology, Shanghai, China
Qingwei Liu, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
Tan Chen, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Key Laboratory of Molecular Virology and Immunology, Shanghai, China
Yingyi Zhang, Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences Chinese Academy of Sciences, Shanghai, China
Wen Jiang, Purdue University, Weldon School of Biomedical Engineering, West Lafayette, United StatesFollow
Linqi Zhang, Tsinghua University, School of Medicine, Beijing, China
Zhong Huang, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
Yao Cong, Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences Chinese Academy of Sciences, State Key Laboratory of Molecular Biology, Shanghai, China

Abstract

Enterovirus 71 (EV71) is the main pathogen responsible for hand, foot and mouth disease with severe neurological complications and even death in young children. We have recently identified a highly potent anti-EV71 neutralizing monoclonal antibody, termed D5. Here we investigated the structural basis for recognition of EV71 by the antibody D5. Four three-dimensional structures of EV71 particles in complex with IgG or Fab of D5 were reconstructed by cryo-electron microscopy (cryo-EM) single particle analysis all at subnanometer resolutions. The most critical EV71 mature virion-Fab structure was resolved to a resolution of 4.8 Å, which is rare in cryo-EM studies of virus-antibody complex so far. The structures reveal a bivalent binding pattern of D5 antibody across the icosahedral 2-fold axis on mature virion, suggesting that D5 binding may rigidify virions to prevent their conformational changes required for subsequent RNA release. Moreover, we also identified that the complementary determining region 3 (CDR3) of D5 heavy chain directly interacts with the extremely conserved VP1 GH-loop of EV71, which was validated by biochemical and virological assays. We further showed that D5 is indeed able to neutralize a variety of EV71 genotypes and strains. Moreover, D5 could potently confer protection in a mouse model of EV71 infection. Since the conserved VP1 GH-loop is involved in EV71 binding with its uncoating receptor, the scavenger receptor class B, member 2 (SCARB2), the broadly neutralizing ability of D5 might attribute to its inhibition of EV71 from binding SCARB2. Altogether, our results elucidate the structural basis for the binding and neutralization of EV71 by the broadly neutralizing antibody D5, thereby enhancing our understanding of antibody-based protection against EV71 infection. © 2016 Ye et al.

Comments

Ye, X., Fan, C., Ku, Z., Zuo, T., Kong, L., Zhang, C., Shi, J., Liu, Q., Chen, T., Zhang, Y., Jiang, W., Zhang, L., Huang, Z., Cong, Y. Structural Basis for Recognition of Human Enterovirus 71 by a Bivalent Broadly Neutralizing Monoclonal Antibody. PLoS Pathogens Volume 12, Issue 3, March 2016, Article number e1005454, 21p

http://dx.doi.org/10.1371/journal.ppat.1005454

(CC BY 4.0)

Date of this Version

2016

DOI

10.1371/journal.ppat.1005454

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