title: Structure of a hepatitis C virus RNA domain in complex with a translation inhibitor reveals a binding mode reminiscent of riboswitches.
abstract: The internal ribosome entry site (IRES) in the hepatitis C virus (HCV) RNA genome is essential for the initiation of viral protein synthesis. IRES domains adopt well-defined folds that are potential targets for antiviral translation inhibitors. We have determined the three-dimensional structure of the IRES subdomain IIa in complex with a benzimidazole translation inhibitor at 2.2 Å resolution. Comparison to the structure of the unbound RNA in conjunction with studies of inhibitor binding to the target in solution demonstrate that the RNA undergoes a dramatic ligand-induced conformational adaptation to form a deep pocket that resembles the substrate binding sites in riboswitches. The presence of a well-defined ligand-binding pocket within the highly conserved IRES subdomain IIa holds promise for the development of unique anti-HCV drugs with a high barrier to resistance.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Sergey M
authors.initials: SM
authors.lastname: Dibrov
authors.forename: Kejia
authors.initials: K
authors.lastname: Ding
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Brunn
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Parker
authors.forename: B Mikael
authors.initials: BM
authors.lastname: Bergdahl
authors.forename: David L
authors.initials: DL
authors.lastname: Wyles
authors.forename: Thomas
authors.initials: T
authors.lastname: Hermann
mesh_terms: D001562:Benzimidazoles / Q000494:pharmacology; D031541:Fluorescence Resonance Energy Transfer; D016174:Hepacivirus / Q000235:genetics*; D008024:Ligands; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D014176:Protein Biosynthesis / Q000187:drug effects; D012367:RNA, Viral / Q000737:chemistry*; D058928:Riboswitch
chemical_list: D001562:Benzimidazoles; D008024:Ligands; D012367:RNA, Viral; D058928:Riboswitch