Abstract
The hepatitis C virus (HCV) internal ribosome entry site (IRES) is recognized specifically by the small ribosomal subunit and eukaryotic initiation factor 3 (eIF3) before viral translation initiation. Using extensive mutagenesis and structure probing analysis, we show that the eIF3-binding domain of the HCV IRES contains an internal loop structure (loop IIIb) and an adjacent mismatched helix that are important for IRES-dependent initiation of translation. NMR studies reveal a unique three-dimensional structure for this internal loop that is conserved between viral isolates of varying primary sequence in this region. These data indicate that internal loop IIIb may be an attractive target for structure-based design of new antiviral agents.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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5' Untranslated Regions / chemistry
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5' Untranslated Regions / genetics
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5' Untranslated Regions / metabolism
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Antiviral Agents
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Base Pair Mismatch
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Base Sequence
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Binding Sites
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Conserved Sequence* / genetics
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Drug Design
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Genes, Viral / genetics
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Hepacivirus / genetics*
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Magnetic Resonance Spectroscopy
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Models, Molecular
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Nucleic Acid Conformation*
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Peptide Initiation Factors / metabolism*
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Point Mutation / genetics
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Prokaryotic Initiation Factor-3
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Protein Binding
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Protein Biosynthesis
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RNA, Viral / chemistry*
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RNA, Viral / genetics
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RNA, Viral / metabolism*
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Ribosomes / metabolism*
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Structure-Activity Relationship
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Viral Proteins / biosynthesis
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Viral Proteins / genetics
Substances
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5' Untranslated Regions
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Antiviral Agents
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Peptide Initiation Factors
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Prokaryotic Initiation Factor-3
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RNA, Viral
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Viral Proteins