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  • STD NMR spectroscopy and molecular modeling investigation of the binding of N-acetylneuraminic acid derivatives to rhesus rotavirus VP8* core

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    Author(s)
    Haselhorst, Thomas
    Blanchard, Helen
    Frank, Martin
    Kraschnefski, Mark J
    Kiefel, Milton J
    Szyczew, Alex J
    Dyason, Jeffery C
    Fleming, Fiona
    Holloway, Gavan
    Coulson, Barbara S
    von Itzstein, Mark
    Griffith University Author(s)
    von Itzstein, Mark
    Kiefel, Milton
    Haselhorst, Thomas E.
    Year published
    2007
    Metadata
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    Abstract
    The VP8* subunit of rotavirus spike protein VP4 contains a sialic acid (Sia)-binding domain important for host cell attachment and infection. In this study, the binding epitope of the N-acetylneuraminic acid (Neu5Ac) derivatives has been characterized by saturation transfer difference (STD) nuclear magnetic resonance (NMR) spectroscopy. From this STD NMR data, it is proposed that the VP8* core recognizes an identical binding epitope in both methyl -D-N-acetylneuraminide (Neu5Ac2Me) and the disaccharide methyl S-(-D-N-acetylneuraminosyl)-(26)-6-thio-߭D-galactopyranoside (Neu5Ac-(2,6)-S-Gal߱Me). In the VP8*-disaccharide complex, ...
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    The VP8* subunit of rotavirus spike protein VP4 contains a sialic acid (Sia)-binding domain important for host cell attachment and infection. In this study, the binding epitope of the N-acetylneuraminic acid (Neu5Ac) derivatives has been characterized by saturation transfer difference (STD) nuclear magnetic resonance (NMR) spectroscopy. From this STD NMR data, it is proposed that the VP8* core recognizes an identical binding epitope in both methyl -D-N-acetylneuraminide (Neu5Ac2Me) and the disaccharide methyl S-(-D-N-acetylneuraminosyl)-(26)-6-thio-߭D-galactopyranoside (Neu5Ac-(2,6)-S-Gal߱Me). In the VP8*-disaccharide complex, the Neu5Ac moiety contributes to the majority of interaction with the protein, whereas the galactose moiety is solvent-exposed. Molecular dynamics calculations of the VP8*-disaccharide complex indicated that the galactose moiety is unable to adopt a conformation that is in close proximity to the protein surface. STD NMR experiments with methyl 9-O-acetyl--D-N-acetylneuraminide (Neu5,9Ac22Me) in complex with rhesus rotavirus (RRV) VP8* revealed that both the N-acetamide and 9-O-acetate moieties are in close proximity to the Sia-binding domain, with the N-acetamide's methyl group being saturated to a larger extent, indicating a closer association with the protein. RRV VP8* does not appear to significantly recognize the unsaturated Neu5Ac derivative [2-deoxy-2,3-didehydro-D-N-acetylneuraminic acid (Neu5Ac2en)]. Molecular modeling of the protein-Neu5Ac2en complex indicates that key interactions between the protein and the unsaturated Neu5Ac derivative when compared with Neu5Ac2Me would not be sustained. Neu5Ac2Me, Neu5Ac-(2,6)-S-Gal߱Me, Neu5,9Ac22Me, and Neu5Ac2en inhibited rotavirus infection of MA104 cells by 61%, 35%, 30%, and 0%, respectively, at 10 mM concentration. NMR spectroscopic, molecular modeling, and infectivity inhibition results are in excellent agreement and provide valuable information for the design of inhibitors of rotavirus infection.
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    Journal Title
    Glycobiology
    Volume
    17
    Issue
    1
    Publisher URI
    http://glycob.oxfordjournals.org/
    DOI
    https://doi.org/10.1093/glycob/cwl051
    Copyright Statement
    This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Glycobiology following peer review. The definitive publisher-authenticated version Glycobiology, Vol. 17(1), pp. 68-81 is available online at: http://dx.doi.org/10.1093/glycob/cwl051
    Subject
    Biological sciences
    Biomedical and clinical sciences
    Biochemistry and cell biology
    Publication URI
    http://hdl.handle.net/10072/13720
    Collection
    • Journal articles

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