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A sensor-adaptor mechanism for enterovirus uncoating from structures of EV71

Nature Structural & Molecular Biology volume 19, pages 424429 (2012) | Download Citation

Abstract

Enterovirus 71 (EV71) is a major agent of hand, foot and mouth disease in children that can cause severe central nervous system disease and death. No vaccine or antiviral therapy is available. High-resolution structural analysis of the mature virus and natural empty particles shows that the mature virus is structurally similar to other enteroviruses. In contrast, the empty particles are markedly expanded and resemble elusive enterovirus-uncoating intermediates not previously characterized in atomic detail. Hydrophobic pockets in the EV71 capsid are collapsed in this expanded particle, providing a detailed explanation of the mechanism for receptor-binding triggered virus uncoating. These structures provide a model for enterovirus uncoating in which the VP1 GH loop acts as an adaptor-sensor for cellular receptor attachment, converting heterologous inputs to a generic uncoating mechanism, highlighting new opportunities for therapeutic intervention.

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Acknowledgements

We thank Sinovac Biotech Ltd. and the China National Biotech Group for providing virus samples, R. Gilbert for assistance with analytical ultracentrifugation, R. Esnouf for help with pocket analysis, J. Grimes for various help, especially with VEDA, and A. Kotecha for assistance with Diamond data collection. We also thank the Photon Factory, Japan, and the National Synchrotron Radiation Laboratory (NSRL), China. Work was supported by the National Major Project of Infectious Disease, the Ministry of Science and the Technology 973 Project (grant no. 2007CB914304). D.I.S., E.E.F. and T.S.W. are supported by the UK Medical Research Council, J.R. by the Wellcome Trust and C.P. by the Department for Environment, Food and Rural Affairs (DEFRA, UK).

Author information

Author notes

    • Xiangxi Wang
    • , Wei Peng
    •  & Jingshan Ren

    These authors contributed equally to this work.

Affiliations

  1. National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing, China.

    • Xiangxi Wang
    • , Wei Peng
    • , Jiwei Xu
    • , Xumei Li
    •  & Zihe Rao
  2. Division of Structural Biology, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Headington, Oxford, UK.

    • Jingshan Ren
    • , Claudine Porta
    • , Thomas S Walter
    • , David I Stuart
    •  & Elizabeth E Fry
  3. National Institutes for Food and Drug Control, No. 2 Tiantan Xili, Beijing, China.

    • Zhongyu Hu
    • , Weidong Yin
    • , Xinliang Shen
    •  & Junzhi Wang
  4. Laboratory of Structural Biology, School of Medicine, Tsinghua University, Beijing, China.

    • Zhiyong Lou
    •  & Zihe Rao
  5. Diamond Light Sources, Harwell Science and Innovation Campus, Didcot, UK.

    • Gwyndaf Evans
    • , Danny Axford
    • , Robin Owen
    •  & David I Stuart
  6. Institute of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK.

    • David J Rowlands

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Contributions

J.W., Z.H., W.Y. and X.S. prepared samples; X.W., W.P., X.L., Z.L., J.X., J.R., C.P., G.E., D.A., R.O., T.S.W., E.E.F. and D.I.S. performed research; W.P., X.W., Z.L., J.R., E.E.F. and D.I.S. analyzed data and, with D.J.R. and Z.R., wrote the manuscript, in discussion with J.W., Z.H., W.Y. and X.S.; all authors contributed to experimental design; Z.R. and D.I.S. supervised the project.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Junzhi Wang or David I Stuart or Elizabeth E Fry or Zihe Rao.

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DOI

https://doi.org/10.1038/nsmb.2255

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