{"doi":"10.1101/2023.09.25.558837","title":"Structural and functional insights into the enzymatic plasticity of the SARS-CoV-2 NiRAN Domain","abstract":"The enzymatic activity of the SARS-CoV-2 nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain is essential for viral propagation, with three distinct activities associated with modification of the nsp9 N-terminus, NMPylation, RNAylation, and deRNAylation/capping via a GDP-polyribonucleotidyltransferase reaction. The latter two activities comprise an unconventional mechanism for initiating viral RNA 5'-cap formation, while the role of NMPylation is unclear. The structural mechanisms for these diverse enzymatic activities have not been properly delineated. Here we determine high-resolution cryo-electron microscopy structures of catalytic intermediates for the NMPylation and deRNAylation/capping reactions, revealing diverse nucleotide binding poses and divalent metal ion coordination sites to promote its repertoire of activities. The deRNAylation/capping structure explains why GDP is a preferred substrate for the capping reaction over GTP. Altogether, these findings enhance our understanding of the promiscuous coronaviral NiRAN domain, a therapeutic target, and provide an accurate structural platform for drug development.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":400932,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9576,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1062486,"name":"Olga Fedorova","orcid":"0000-0001-5995-7358","position":1,"is_corresponding":false},{"id":471220,"name":"Paul Dominic B. Olinares","orcid":"0000-0002-3429-6618","position":2,"is_corresponding":false},{"id":893169,"name":"Joshua Chandanani","orcid":"0000-0003-2671-2412","position":3,"is_corresponding":false},{"id":589015,"name":"Anoosha Banerjee","orcid":null,"position":4,"is_corresponding":false},{"id":631128,"name":"Young Joo Choi","orcid":"0000-0001-9902-2979","position":5,"is_corresponding":false},{"id":106394,"name":"Henrik Molina","orcid":"0000-0001-8950-4990","position":6,"is_corresponding":false},{"id":51698,"name":"Brian T. Chait","orcid":"0000-0003-3524-557X","position":7,"is_corresponding":false},{"id":258065,"name":"Seth A. Darst","orcid":"0000-0002-8241-3153","position":8,"is_corresponding":false},{"id":461537,"name":"Elizabeth A. Campbell","orcid":"0000-0002-1332-128X","position":9,"is_corresponding":false},{"id":562819,"name":"Gabriel I. Small","orcid":"0000-0002-3506-5256","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-19T01:20:08.195423Z","pmid":"37808858","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}