| Structural and functional basis of resistance to neuraminidase inhibitors of influenza B viruses. | |
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MedLine Citation:
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PMID: 20695427 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We have identified a virus, B/Perth/211/2001, with a spontaneous mutation, D197E in the neuraminidase (NA), which confers cross-resistance to all NA inhibitors. We analyzed enzyme properties of the D197 and E197 NAs and compared these to a D197N NA, known to arise after oseltamivir treatment. Zanamivir and peramivir bound slowly to the wild type NA, but binding of oseltamivir was more rapid. The D197E/N mutations resulted in faster binding of all three inhibitors. Analysis of the crystal structures of D197 and E197 NAs with and without inhibitors showed that the D197E mutation compromised the interaction of neighboring R150 with the N-acetyl group, common to the substrate sialic acid and all NA inhibitors. Although rotation of the E275 in the NA active site occurs upon binding peramivir in both the D197 and E197 NAs, this does not occur upon binding oseltamivir in the E197 NA. Lack of the E275 rotation would also account for the loss of slow binding and the partial resistance of influenza B wild type NAs to oseltamivir. |
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Authors:
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Aaron J Oakley; Susan Barrett; Thomas S Peat; Janet Newman; Victor A Streltsov; Lynne Waddington; Takehiko Saito; Masato Tashiro; Jennifer L McKimm-Breschkin |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: 53 ISSN: 1520-4804 ISO Abbreviation: J. Med. Chem. Publication Date: 2010 Sep |
Date Detail:
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Created Date: 2010-09-02 Completed Date: 2010-09-30 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: United States |
Other Details:
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Languages: eng Pagination: 6421-31 Citation Subset: IM |
Affiliation:
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CSIRO Materials Science and Engineering, Parkville, 343 Royal Parade, Parkville, Victoria, 3052, Australia. |
| Data Bank Information | |
Bank Name/Acc. No.:
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PDB/3K36; 3K37; 3K38; 3K39; 3K3A |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antiviral Agents
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chemistry* Crystallography, X-Ray Cyclopentanes / chemistry* Drug Resistance, Viral* Guanidines / chemistry* Hydrogen Bonding Influenza B virus / enzymology* Models, Molecular Molecular Structure Mutation Neuraminidase / antagonists & inhibitors*, chemistry*, genetics Oseltamivir / chemistry* Protein Binding Zanamivir / chemistry* |
| Grant Support | |
ID/Acronym/Agency:
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R01A1062721//PHS HHS |
| Chemical | |
Reg. No./Substance:
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0/Antiviral Agents; 0/Cyclopentanes; 0/Guanidines; 0/Oseltamivir; 0/peramivir; 139110-80-8/Zanamivir; EC 3.2.1.18/Neuraminidase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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