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dc.contributor.authorHaselhorst, Thomasen_US
dc.contributor.authorBlanchard, Helenen_US
dc.contributor.authorFrank, Martinen_US
dc.contributor.authorKraschnefski, Marken_US
dc.contributor.authorKiefel, Miltonen_US
dc.contributor.authorSzyczew, Alexanderen_US
dc.contributor.authorDyason, Jeffreyen_US
dc.contributor.authorFleming, Fionaen_US
dc.contributor.authorHolloway, Gavanen_US
dc.contributor.authorS. Coulson, Barbaraen_US
dc.contributor.authorvon Itzstein, Marken_US
dc.date.accessioned2017-04-24T07:56:30Z
dc.date.available2017-04-24T07:56:30Z
dc.date.issued2006en_US
dc.date.modified2009-09-08T08:04:15Z
dc.identifier.issn09596658en_US
dc.identifier.doi10.1093/glycob/cwl051en_AU
dc.identifier.urihttp://hdl.handle.net/10072/13720
dc.description.abstractThe 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.en_US
dc.description.peerreviewedYesen_US
dc.description.publicationstatusYesen_AU
dc.format.extent1221371 bytes
dc.format.mimetypeapplication/pdf
dc.languageEnglishen_US
dc.language.isoen_AU
dc.publisherOxford University Pressen_US
dc.publisher.placeOxford, UKen_US
dc.publisher.urihttp://glycob.oxfordjournals.org/en_AU
dc.relation.ispartofstudentpublicationNen_AU
dc.relation.ispartofpagefrom68en_US
dc.relation.ispartofpageto81en_US
dc.relation.ispartofissue1en_US
dc.relation.ispartofjournalGlycobiologyen_US
dc.relation.ispartofvolume17en_US
dc.rights.retentionYen_AU
dc.subject.fieldofresearchcode249901en_US
dc.subject.fieldofresearchcode250105en_US
dc.subject.fieldofresearchcode320302en_US
dc.titleSTD NMR spectroscopy and molecular modeling investigation of the binding of N-acetylneuraminic acid derivatives to rhesus rotavirus VP8* coreen_US
dc.typeJournal articleen_US
dc.type.descriptionC1 - Peer Reviewed (HERDC)en_US
dc.type.codeC - Journal Articlesen_US
gro.rights.copyrightThis 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/cwl051en_AU
gro.date.issued2006
gro.hasfulltextFull Text


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