{"doi":"10.1101/2020.12.17.423260","title":"Higher-order structures of the foot-and-mouth disease virus RNA-dependent RNA polymerase required for dynamic inter-molecular interactions involved in viral genome replication","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  Replication of many positive-sense RNA viruses occurs within intracellular membrane-associated compartments. These are believed to provide a favourable environment for replication to occur, concentrating essential viral structural and non-structural components, as well as protecting these components from host-cell pathogen recognition and innate immune responses. However, the details of the molecular interactions and dynamics within these structures is very limited. One of the key components of the replication machinery is the RNA-dependent RNA polymerase, RdRp. This enzyme has been shown to form higher-order fibrils\n                  <jats:italic>in vitro</jats:italic>\n                  . Here, using the RdRp from foot-and-mouth disease virus (termed 3D\n                  <jats:sup>pol</jats:sup>\n                  ), we report fibril structures, solved at ~7-9 Å resolution by cryo-EM, revealing multiple conformations of a flexible assembly. Fitting high-resolution coordinates led to the definition of potential intermolecular interactions. We employed mutagenesis using a sub-genomic replicon system to probe the importance of these interactions for replication. We use these data to propose models for the role of higher order 3D\n                  <jats:sup>pol</jats:sup>\n                  complexes as a dynamic scaffold within which RNA replication can occur.\n                </jats:p>","journal":null,"year":null,"id":675437,"datarank":0.13350821327500995,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.029536136191018147,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.029536136191018147,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":1,"citers_with_citation_signal":1,"citers_with_endowment":1,"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":668968,"name":"James Streetley","orcid":"0000-0001-7808-605X","position":1,"is_corresponding":false},{"id":1146864,"name":"Morgan R. Herod","orcid":"0000-0002-8626-6787","position":2,"is_corresponding":false},{"id":307206,"name":"Rebecca F. Thompson","orcid":"0000-0002-4254-8854","position":3,"is_corresponding":false},{"id":611115,"name":"Mark Harris","orcid":"0000-0002-9821-1003","position":4,"is_corresponding":false},{"id":668977,"name":"David Bhella","orcid":"0000-0003-2096-8310","position":5,"is_corresponding":false},{"id":925608,"name":"Nicola J. Stonehouse","orcid":"0000-0003-1146-5519","position":6,"is_corresponding":false},{"id":1764787,"name":"Eleni-Anna Loundras","orcid":"0000-0002-3485-3111","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Higher-order structures of the foot-and-mouth disease virus RNA-dependent RNA polymerase required for dynamic inter-molecular interactions involved in viral genome replication","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  Replication of many positive-sense RNA viruses occurs within intracellular membrane-associated compartments. These are believed to provide a favourable environment for replication to occur, concentrating essential viral structural and non-structural components, as well as protecting these components from host-cell pathogen recognition and innate immune responses. However, the details of the molecular interactions and dynamics within these structures is very limited. One of the key components of the replication machinery is the RNA-dependent RNA polymerase, RdRp. This enzyme has been shown to form higher-order fibrils\n                  <jats:italic>in vitro</jats:italic>\n                  . Here, using the RdRp from foot-and-mouth disease virus (termed 3D\n                  <jats:sup>pol</jats:sup>\n                  ), we report fibril structures, solved at ~7-9 Å resolution by cryo-EM, revealing multiple conformations of a flexible assembly. Fitting high-resolution coordinates led to the definition of potential intermolecular interactions. We employed mutagenesis using a sub-genomic replicon system to probe the importance of these interactions for replication. We use these data to propose models for the role of higher order 3D\n                  <jats:sup>pol</jats:sup>\n                  complexes as a dynamic scaffold within which RNA replication can occur.\n                </jats:p>","is_dataset_classified":null,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"26207759","pmcid":null,"openalex_id":"https://openalex.org/W3110729024","authors":[],"funders":[{"funder_name":"Wellcome Trust","grant_id":"108466","title":"Modern Cryo-Electron Microscopy with Direct Electron Detection at the University of Leeds."},{"funder_name":"UK Research and Innovation","grant_id":"MR/S007229/1","title":"Functions of Norovirus VP1: A Multi-Faceted Capsid Protein"},{"funder_name":"Wellcome Trust","grant_id":"096670","title":"Coordinated use of the hepatitis C virus genome during the virus lifecycle."},{"funder_name":"UK Research and Innovation","grant_id":"MR/M000451/1","title":"A structure analysis of the intact virion and replicative complexes of human respiratory syncytial virus"},{"funder_name":"UK Research and Innovation","grant_id":"BB/P001459/1","title":"Understanding the catalytic and non-catalytic roles of the essential 3D protein in the FMDV replication complex"}],"total_grants":5,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[{"year":2021,"count":1}],"oa_status":"green","license":"cc-by-nc-nd","oa_locations":[{"url":"https://www.biorxiv.org/content/biorxiv/early/2020/12/18/2020.12.17.423260.1.full.pdf","host_type":"repository"},{"url":"https://www.biorxiv.org/content/biorxiv/early/2020/12/18/2020.12.17.423260.1.full.pdf","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.1101/2020.12.17.423260","host_type":"publisher"},{"url":"https://doi.org/10.1101/2020.12.17.423260","host_type":"repository"},{"url":"https://dx.doi.org/10.1101/2020.12.17.423260","host_type":""}],"fields_of_study":["Viral Infections and Immunology Research","Animal Disease Management and Epidemiology","RNA and protein synthesis mechanisms","0301 basic medicine","0303 health sciences","03 medical and health sciences"],"mesh_terms":[],"keywords":["Biology","RNA","Replicon","RNA-dependent RNA polymerase","Polymerase","Viral replication","RNA polymerase","Cell biology","Mutagenesis","Computational biology","Virus","Genome","Genetics","Mutation","Gene"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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