title: A conserved RNA structure within the HCV IRES eIF3-binding site.
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.
authors.affiliation: RiboTargets Ltd., Granta Park, Abington, Cambridge, CB1 6GB, UK.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Collier
authors.forename: José
authors.initials: J
authors.lastname: Gallego
authors.forename: Roscoe
authors.initials: R
authors.lastname: Klinck
authors.forename: Paul T
authors.initials: PT
authors.lastname: Cole
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Harris
authors.forename: Geoffrey P
authors.initials: GP
authors.lastname: Harrison
authors.forename: Fareed
authors.initials: F
authors.lastname: Aboul-Ela
authors.forename: Gabriele
authors.initials: G
authors.lastname: Varani
authors.forename: Stephen
authors.initials: S
authors.lastname: Walker
mesh_terms: D020121:5' Untranslated Regions / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000998:Antiviral Agents; D020137:Base Pair Mismatch; D001483:Base Sequence; D001665:Binding Sites; D017124:Conserved Sequence / Q000235:genetics; D015195:Drug Design; D005814:Genes, Viral / Q000235:genetics; D016174:Hepacivirus / Q000235:genetics*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D010448:Peptide Initiation Factors / Q000378:metabolism*; D017354:Point Mutation / Q000235:genetics; D039665:Prokaryotic Initiation Factor-3; D011485:Protein Binding; D014176:Protein Biosynthesis; D012367:RNA, Viral / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D012270:Ribosomes / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D020121:5' Untranslated Regions; D000998:Antiviral Agents; D010448:Peptide Initiation Factors; D039665:Prokaryotic Initiation Factor-3; D012367:RNA, Viral; D014764:Viral Proteins