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Receptor binding by a ferret-transmissible H5 avian influenza virus

Nature volume 497, pages 392396 (16 May 2013) | Download Citation


Cell-surface-receptor binding by influenza viruses is a key determinant of their transmissibility, both from avian and animal species to humans as well as from human to human. Highly pathogenic avian H5N1 viruses that are a threat to public health have been observed to acquire affinity for human receptors, and transmissible-mutant-selection experiments have identified a virus that is transmissible in ferrets1,2,3, the generally accepted experimental model for influenza in humans. Here, our quantitative biophysical measurements of the receptor-binding properties of haemagglutinin (HA) from the transmissible mutant indicate a small increase in affinity for human receptor and a marked decrease in affinity for avian receptor. From analysis of virus and HA binding data we have derived an algorithm that predicts virus avidity from the affinity of individual HA–receptor interactions. It reveals that the transmissible-mutant virus has a 200-fold preference for binding human over avian receptors. The crystal structure of the transmissible-mutant HA in complex with receptor analogues shows that it has acquired the ability to bind human receptor in the same folded-back conformation as seen for HA from the 1918, 1957 (ref. 4), 1968 (ref. 5) and 2009 (ref. 6) pandemic viruses. This binding mode is substantially different from that by which non-transmissible wild-type H5 virus HA binds human receptor. The structure of the complex also explains how the change in preference from avian to human receptors arises from the Gln226Leu substitution, which facilitates binding to human receptor but restricts binding to avian receptor. Both features probably contribute to the acquisition of transmissibility by this mutant virus.

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Data deposits

Structural data have been deposited with the Protein Data Bank under accession codes 4BGW, 4BGX, 4BGY, 4BGZ, 4BH0, 4BH1, 4BH2, 4BH3 and 4BH4.


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We are grateful to staff at the Diamond Light Source Synchrotron for assistance and beamline access under proposal 7707, E. Christodoulou and S. Vachieri for discussions on protein expression, the staff of the NIMR Large Scale Laboratory, L Haire for assistance with crystallization experiments and S. Smerdon and P. Rosenthal for discussions. H.X. was supported by BBSRC (award number BB/E010806). This work was funded by the Medical Research Council through programmes U117584222, U117512723 and U117570592.

Author information

Author notes

    • Xiaoli Xiong
    • , Peter J. Coombs
    •  & Stephen R. Martin

    These authors contributed equally to this work.

    • Haixia Xiao

    Present address: Laboratory of Protein Engineering and Vaccines, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China.


  1. MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK

    • Xiaoli Xiong
    • , Peter J. Coombs
    • , Stephen R. Martin
    • , Haixia Xiao
    • , John W. McCauley
    • , Philip A. Walker
    • , Patrick J. Collins
    • , John J. Skehel
    •  & Steven J. Gamblin
  2. Ministry of Agriculture, Key Laboratory of Plant Pathology, China Agricultural University, Yuanmingyuanxilu, 2, Beijing 100193, China

    • Junfeng Liu
  3. Novartis Institutes for BioMedical Research, Klybeckstrasse 141, CH-4057 Basel, Switzerland

    • Kathrin Locher
  4. Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53711, USA

    • Yoshihiro Kawaoka


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X.X., P.J.C., S.R.M., J.L., H.X., J.W.M., K.L., P.A.W., P.C., Y.K., J.J.S. and S.J.G. all performed experiments and contributed to the writing of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to John J. Skehel or Steven J. Gamblin.

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    Supplementary Information

    This file contains Supplementary Figures 1 and 2A-I with additional Supplementary Text and Data and Supplementary Tables 1, 1B, 2a, 2b and additional references.

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