title: Molecular architecture of the ribosome-bound Hepatitis C Virus internal ribosomal entry site RNA.
abstract: Internal ribosomal entry sites (IRESs) are structured cis-acting RNAs that drive an alternative, cap-independent translation initiation pathway. They are used by many viruses to hijack the translational machinery of the host cell. IRESs facilitate translation initiation by recruiting and actively manipulating the eukaryotic ribosome using only a subset of canonical initiation factor and IRES transacting factors. Here we present cryo-EM reconstructions of the ribosome 80S- and 40S-bound Hepatitis C Virus (HCV) IRES. The presence of four subpopulations for the 80S•HCV IRES complex reveals dynamic conformational modes of the complex. At a global resolution of 3.9 Å for the most stable complex, a derived atomic model reveals a complex fold of the IRES RNA and molecular details of its interaction with the ribosome. The comparison of obtained structures explains how a modular architecture facilitates mRNA loading and tRNA binding to the P-site. This information provides the structural foundation for understanding the mechanism of HCV IRES RNA-driven translation initiation.
authors.affiliation: Institut für Medizinische Physik und Biophysik, Charité - Universitätsmedizin, Berlin, Germany.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Institut für Medizinische Physik und Biophysik, Charité - Universitätsmedizin, Berlin, Germany.
authors.forename: Marianne
authors.initials: M
authors.lastname: Collier
authors.affiliation: Institut für Medizinische Physik und Biophysik, Charité - Universitätsmedizin, Berlin, Germany.
authors.forename: Justus
authors.initials: J
authors.lastname: Loerke
authors.affiliation: Institut für Medizinische Physik und Biophysik, Charité - Universitätsmedizin, Berlin, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Ismer
authors.affiliation: Institut für Medizinische Physik und Biophysik, Charité - Universitätsmedizin, Berlin, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schmidt
authors.affiliation: Institut für Medizinische Physik und Biophysik, Charité - Universitätsmedizin, Berlin, Germany.
authors.forename: Tarek
authors.initials: T
authors.lastname: Hilal
authors.affiliation: Institut für Medizinische Physik und Biophysik, Charité - Universitätsmedizin, Berlin, Germany.
authors.forename: Thiemo
authors.initials: T
authors.lastname: Sprink
authors.affiliation: Institut für Medizinische Physik und Biophysik, Charité - Universitätsmedizin, Berlin, Germany.
authors.forename: Kaori
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Institut für Medizinische Physik und Biophysik, Charité - Universitätsmedizin, Berlin, Germany UltraStrukturNetzwerk, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Mielke
authors.affiliation: Institut für Medizinische Physik und Biophysik, Charité - Universitätsmedizin, Berlin, Germany UltraStrukturNetzwerk, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Bürger
authors.affiliation: Structural Biology Programme, CEITEC, Masaryk University, Brno, Czech Republic.
authors.forename: Tanvir R
authors.initials: TR
authors.lastname: Shaikh
authors.affiliation: Institut für Medizinische Physik und Biophysik, Charité - Universitätsmedizin, Berlin, Germany.
authors.forename: Marylena
authors.initials: M
authors.lastname: Dabrowski
authors.affiliation: Institut für Medizinische Physik und Biophysik, Charité - Universitätsmedizin, Berlin, Germany.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Hildebrand
authors.affiliation: Institut für Medizinische Physik und Biophysik, Charité - Universitätsmedizin, Berlin, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Scheerer
authors.affiliation: Institut für Medizinische Physik und Biophysik, Charité - Universitätsmedizin, Berlin, Germany christian.spahn@charite.de.
authors.forename: Christian M T
authors.initials: CM
authors.lastname: Spahn
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D006526:Hepatitis C / Q000378:metabolism; D006801:Humans; D000067556:Internal Ribosome Entry Sites; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D012367:RNA, Viral / Q000737:chemistry*; D054657:Ribosome Subunits / Q000737:chemistry*
chemical_list: D000067556:Internal Ribosome Entry Sites; D012367:RNA, Viral
keywords: 80S ribosome; IRES RNA; cryo‐electron microscopy; internal initiation; translational control