{"doi":"10.1038/ncomms8646","title":"Cryo-EM structure of Hepatitis C virus IRES bound to the human ribosome at 3.9-Å resolution","abstract":"<jats:title>Abstract</jats:title><jats:p>Hepatitis C virus (HCV), a widespread human pathogen, is dependent on a highly structured 5′-untranslated region of its mRNA, referred to as internal ribosome entry site (IRES), for the translation of all of its proteins. The HCV IRES initiates translation by directly binding to the small ribosomal subunit (40S), circumventing the need for many eukaryotic translation initiation factors required for mRNA scanning. Here we present the cryo-EM structure of the human 40S ribosomal subunit in complex with the HCV IRES at 3.9 Å resolution, determined by focused refinement of an 80S ribosome–HCV IRES complex. The structure reveals the molecular details of the interactions between the IRES and the 40S, showing that expansion segment 7 (ES7) of the 18S rRNA acts as a central anchor point for the HCV IRES. The structural data rationalizes previous biochemical and genetic evidence regarding the initiation mechanism of the HCV and other related IRESs.</jats:p>","journal":"Nature Communications","year":2015,"id":589343,"datarank":4.773621840554143,"base_score":4.976733742420574,"endowment":4.976733742420574,"self_citation_contribution":0.7465100613630863,"citation_network_contribution":4.027111779191057,"self_endowment_contribution":0.7465100613630863,"citer_contribution":4.027111779191057,"corpus_percentile":null,"corpus_rank":null,"citation_count":144,"citer_count":140,"citers_with_citation_signal":128,"citers_with_endowment":128,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":189114,"name":"Daniel Boehringer","orcid":null,"position":1,"is_corresponding":false},{"id":189115,"name":"Marc Leibundgut","orcid":null,"position":2,"is_corresponding":false},{"id":1507853,"name":"Joop van den Heuvel","orcid":null,"position":3,"is_corresponding":false},{"id":679831,"name":"Nenad Ban","orcid":"0000-0002-9527-210X","position":4,"is_corresponding":false},{"id":1507852,"name":"Nick Quade","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Cryo-EM structure of Hepatitis C virus IRES bound to the human ribosome at 3.9-Å resolution","abstract":"<jats:title>Abstract</jats:title><jats:p>Hepatitis C virus (HCV), a widespread human pathogen, is dependent on a highly structured 5′-untranslated region of its mRNA, referred to as internal ribosome entry site (IRES), for the translation of all of its proteins. The HCV IRES initiates translation by directly binding to the small ribosomal subunit (40S), circumventing the need for many eukaryotic translation initiation factors required for mRNA scanning. Here we present the cryo-EM structure of the human 40S ribosomal subunit in complex with the HCV IRES at 3.9 Å resolution, determined by focused refinement of an 80S ribosome–HCV IRES complex. The structure reveals the molecular details of the interactions between the IRES and the 40S, showing that expansion segment 7 (ES7) of the 18S rRNA acts as a central anchor point for the HCV IRES. The structural data rationalizes previous biochemical and genetic evidence regarding the initiation mechanism of the HCV and other related IRESs.</jats:p>","is_dataset_classified":null,"base_score":4.976733742420574,"endowment":4.976733742420574,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"26155016","pmcid":"PMC4510694","openalex_id":"https://openalex.org/W2121649191","authors":[],"funders":[{"funder_name":"European Research Council","grant_id":"250071","title":"Structural studies of the eukaryotic ribosome by X-ray crystallography"},{"funder_name":"National Institutes of Health","grant_id":"5P41RR001081-29","title":"FUNCTIONAL PROMISCUITY IN O-SUCCINYLBENZOATE SYNTHASE"},{"funder_name":"Swiss National Science Foundation","grant_id":"144214","title":"Structural studies of eukaryotic complexes involved in ribosome assembly and translation initiation"},{"funder_name":"European Commission","grant_id":"279039","title":"New Technologies and Production Tools for Complex Protein Biologics"}],"total_grants":4,"fwci":6.8872,"citation_percentile":0.97727974,"influential_citations":0,"citation_trend":[{"year":2015,"count":4},{"year":2016,"count":12},{"year":2017,"count":17},{"year":2018,"count":17},{"year":2019,"count":14},{"year":2020,"count":14},{"year":2021,"count":10},{"year":2022,"count":13},{"year":2023,"count":9},{"year":2024,"count":5},{"year":2025,"count":23},{"year":2026,"count":6}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.nature.com/articles/ncomms8646.pdf","host_type":"journal"},{"url":"https://www.nature.com/articles/ncomms8646.pdf","host_type":"publisher"},{"url":"https://www.nature.com/articles/ncomms8646","host_type":"publisher"},{"url":"https://doi.org/10.1038/ncomms8646","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/26155016","host_type":"repository"},{"url":"http://hdl.handle.net/20.500.11850/103868","host_type":"repository"},{"url":"http://hdl.handle.net/10033/561176","host_type":"repository"},{"url":"http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.790.5750","host_type":""},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/4510694","host_type":"repository"},{"url":"https://doi.org/10.3929/ethz-b-000103868","host_type":"repository"},{"url":"https://repository.helmholtz-hzi.de/bitstream/10033/561176/1/Quade%20et%20al_final.pdf","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC4510694","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC4510694?pdf=render","host_type":"Europe_PMC"},{"url":"https://dx.doi.org/10.3929/ethz-b-000103868","host_type":""},{"url":"http://dx.doi.org/10.1038/ncomms8646","host_type":""},{"url":"https://dx.doi.org/10.1038/ncomms8646","host_type":""},{"url":"https://sonar.ch/global/documents/181138","host_type":""},{"url":"http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4510694/","host_type":""}],"fields_of_study":["RNA and protein synthesis mechanisms","Viral Infections and Immunology Research","RNA modifications and cancer","0301 basic medicine","0303 health sciences","03 medical and health sciences","Binding Sites","Cryoelectron Microscopy","Gene Expression Regulation, Viral","Hepacivirus","Humans","Internal Ribosome Entry Sites","Models, Molecular","Peptide Chain Initiation, Translational","RNA, Ribosomal, 18S","Ribosome Subunits, Small, Eukaryotic"],"mesh_terms":["Internal Ribosome Entry Sites","Binding Sites","Humans","Models, Molecular","Peptide Chain Initiation, Translational","RNA, Ribosomal, 18S","Gene Expression Regulation, Viral","Hepacivirus","Cryoelectron Microscopy","Ribosome Subunits, Small, Eukaryotic"],"keywords":["Internal ribosome entry site","Eukaryotic Small Ribosomal Subunit","Translation (biology)","Eukaryotic Ribosome","Five prime untranslated region","Biology","Eukaryotic translation","Ribosome","Virology","Ribosomal RNA","Eukaryotic initiation factor","Ribosomal binding site","Untranslated region","Initiation factor","Computational biology","Cell biology","Messenger RNA","Genetics","RNA","Gene","Gene Expression Regulation, Viral","Models, Molecular","Ribosome Subunits, Small, Eukaryotic","Binding Sites","Cryoelectron Microscopy","Hepacivirus","Internal Ribosome Entry Sites","Article","RNA, Ribosomal, 18S","Humans","Peptide Chain Initiation, Translational"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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