dc.contributor.author | Haselhorst, Thomas | |
dc.contributor.author | Blanchard, Helen | |
dc.contributor.author | Frank, Martin | |
dc.contributor.author | Kraschnefski, Mark J | |
dc.contributor.author | Kiefel, Milton J | |
dc.contributor.author | Szyczew, Alex J | |
dc.contributor.author | Dyason, Jeffery C | |
dc.contributor.author | Fleming, Fiona | |
dc.contributor.author | Holloway, Gavan | |
dc.contributor.author | Coulson, Barbara S | |
dc.contributor.author | von Itzstein, Mark | |
dc.date.accessioned | 2018-01-23T01:00:22Z | |
dc.date.available | 2018-01-23T01:00:22Z | |
dc.date.issued | 2007 | |
dc.date.modified | 2009-09-08T08:04:15Z | |
dc.identifier.issn | 0959-6658 | |
dc.identifier.doi | 10.1093/glycob/cwl051 | |
dc.identifier.uri | http://hdl.handle.net/10072/13720 | |
dc.description.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, 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.peerreviewed | Yes | |
dc.description.publicationstatus | Yes | |
dc.format.extent | 1221371 bytes | |
dc.format.mimetype | application/pdf | |
dc.language | English | |
dc.language.iso | eng | |
dc.publisher | Oxford University Press | |
dc.publisher.place | Oxford, UK | |
dc.publisher.uri | http://glycob.oxfordjournals.org/ | |
dc.relation.ispartofstudentpublication | N | |
dc.relation.ispartofpagefrom | 68 | |
dc.relation.ispartofpageto | 81 | |
dc.relation.ispartofissue | 1 | |
dc.relation.ispartofjournal | Glycobiology | |
dc.relation.ispartofvolume | 17 | |
dc.rights.retention | Y | |
dc.subject.fieldofresearch | Biological sciences | |
dc.subject.fieldofresearch | Biomedical and clinical sciences | |
dc.subject.fieldofresearch | Biochemistry and cell biology | |
dc.subject.fieldofresearchcode | 31 | |
dc.subject.fieldofresearchcode | 32 | |
dc.subject.fieldofresearchcode | 3101 | |
dc.title | STD NMR spectroscopy and molecular modeling investigation of the binding of N-acetylneuraminic acid derivatives to rhesus rotavirus VP8* core | |
dc.type | Journal article | |
dc.type.description | C1 - Articles | |
dc.type.code | C - Journal Articles | |
gro.rights.copyright | 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 | |
gro.date.issued | 2006 | |
gro.hasfulltext | Full Text | |
gro.griffith.author | von Itzstein, Mark | |
gro.griffith.author | Kiefel, Milton | |
gro.griffith.author | Haselhorst, Thomas E. | |