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Crystal structure of the multifunctional paramyxovirus hemagglutinin-neuraminidase

Nature Structural Biology volume 7, pages 1068–1074 (2000)Cite this article

Abstract

Paramyxoviruses are the main cause of respiratory disease in children. One of two viral surface glycoproteins, the hemagglutinin-neuraminidase (HN), has several functions in addition to being the major surface antigen that induces neutralizing antibodies. Here we present the crystal structures of Newcastle disease virus HN alone and in complex with either an inhibitor or with the β-anomer of sialic acid. The inhibitor complex reveals a typical neuraminidase active site within a β-propeller fold. Comparison of the structures of the two complexes reveal differences in the active site, suggesting that the catalytic site is activated by a conformational switch. This site may provide both sialic acid binding and hydrolysis functions since there is no evidence for a second sialic acid binding site in HN. Evidence for a single site with dual functions is examined and supported by mutagenesis studies. The structure provides the basis for the structure-based design of inhibitors for a range of paramyxovirus-induced diseases.

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Figure 1: Schematic representations of the crystal structure of HN.
Figure 2: Structure based sequence alignment of HN from seven paramyxoviruses:
Figure 3: The active site.
Figure 4: Electron density for the HN–ligand complexes.
Figure 5: Comparison of the two crystal forms.
Figure 6: Mapping of seven Mab sites37 onto the surface of NDV HN.
Figure 7: Biological activities of NDV HN mutants.

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Acknowledgements

This work was funded by The Wellcome Trust, the Royal Society, the National Institute of Allergy and Infectious Disease, a Cancer Center Support (CORE) grant, the American Lebanese Syrian Associated charities (ALSAC) of St. Jude Children's Research Hospital and EU TMR/LSF grants for access to the Hamburg and Grenoble synchrotrons. We thank staff at DESY, Hamburg, for their assistance, and the EMBL Grenoble Outstation for providing support for measurements at the ESRF. We thank Walter Ward and Rupert Russell for useful discussions, and Ravi Kartha for carrying out the sialyllactose thin-layer chromatography.

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Authors and Affiliations

  1. Department of Biology and Biochemistry, University of Bath, Bath, BA2 7AY, UK

    Susan Crennell & Garry Taylor

  2. Department of Virology and Molecular Biology, St Jude Children's Research Hospital, 332 North Lauderdale, P.O. Box 318, Memphis, 38101-0318, Tennessee, USA

    Toru Takimoto & Allen Portner

  3. Centre for Biomolecular Sciences, The University of St Andrews, St Andrews, Fife, KY16 9ST, Scotland, UK

    Garry Taylor

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Correspondence to Garry Taylor.

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Crennell, S., Takimoto, T., Portner, A. et al. Crystal structure of the multifunctional paramyxovirus hemagglutinin-neuraminidase . Nat Struct Mol Biol 7, 1068–1074 (2000). https://doi.org/10.1038/81002

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