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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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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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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DOI: https://doi.org/10.1038/81002
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