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dc.contributor.authorHaselhorst, Thomas
dc.contributor.authorBlanchard, Helen
dc.contributor.authorFrank, Martin
dc.contributor.authorKraschnefski, Mark J
dc.contributor.authorKiefel, Milton J
dc.contributor.authorSzyczew, Alex J
dc.contributor.authorDyason, Jeffery C
dc.contributor.authorFleming, Fiona
dc.contributor.authorHolloway, Gavan
dc.contributor.authorCoulson, Barbara S
dc.contributor.authorvon Itzstein, Mark
dc.date.accessioned2018-01-23T01:00:22Z
dc.date.available2018-01-23T01:00:22Z
dc.date.issued2007
dc.date.modified2009-09-08T08:04:15Z
dc.identifier.issn0959-6658
dc.identifier.doi10.1093/glycob/cwl051
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.
dc.description.peerreviewedYes
dc.description.publicationstatusYes
dc.format.extent1221371 bytes
dc.format.mimetypeapplication/pdf
dc.languageEnglish
dc.language.isoeng
dc.publisherOxford University Press
dc.publisher.placeOxford, UK
dc.publisher.urihttp://glycob.oxfordjournals.org/
dc.relation.ispartofstudentpublicationN
dc.relation.ispartofpagefrom68
dc.relation.ispartofpageto81
dc.relation.ispartofissue1
dc.relation.ispartofjournalGlycobiology
dc.relation.ispartofvolume17
dc.rights.retentionY
dc.subject.fieldofresearchBiological sciences
dc.subject.fieldofresearchBiomedical and clinical sciences
dc.subject.fieldofresearchBiochemistry and cell biology
dc.subject.fieldofresearchcode31
dc.subject.fieldofresearchcode32
dc.subject.fieldofresearchcode3101
dc.titleSTD NMR spectroscopy and molecular modeling investigation of the binding of N-acetylneuraminic acid derivatives to rhesus rotavirus VP8* core
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
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/cwl051
gro.date.issued2006
gro.hasfulltextFull Text
gro.griffith.authorvon Itzstein, Mark
gro.griffith.authorKiefel, Milton
gro.griffith.authorHaselhorst, Thomas E.


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