{"doi":"10.1038/s41594-021-00619-0","title":"Cryo-EM structure of SARS-CoV-2 ORF3a in lipid nanodiscs","abstract":"SARS-CoV-2 ORF3a is a putative viral ion channel implicated in autophagy inhibition, inflammasome activation and apoptosis. 3a protein and anti-3a antibodies are found in infected patient tissues and plasma. Deletion of 3a in SARS-CoV-1 reduces viral titer and morbidity in mice, suggesting it could be an effective target for vaccines or therapeutics. Here, we present structures of SARS-CoV-2 3a determined by cryo-EM to 2.1-Å resolution. 3a adopts a new fold with a polar cavity that opens to the cytosol and membrane through separate water- and lipid-filled openings. Hydrophilic grooves along outer helices could form ion-conduction paths. Using electrophysiology and fluorescent ion imaging of 3a-reconstituted liposomes, we observe Ca2+-permeable, nonselective cation channel activity, identify mutations that alter ion permeability and discover polycationic inhibitors of 3a activity. 3a-like proteins are found across coronavirus lineages that infect bats and humans, suggesting that 3a-targeted approaches could treat COVID-19 and other coronavirus diseases. A cryo-EM structure of SARS-CoV-2 ORF3a reveals a new fold conserved in coronaviruses, and functional experiments show ion channel activity that may be important for viral infectivity.","journal":"Nature Structural & Molecular Biology","year":2021,"id":146134,"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":256,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9367,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":620868,"name":"Ben Sorum","orcid":"0000-0001-6742-1094","position":1,"is_corresponding":false},{"id":314026,"name":"Sonali S. Mali","orcid":"0000-0003-0737-813X","position":2,"is_corresponding":false},{"id":620869,"name":"Christopher Hoel","orcid":"0000-0002-1344-0780","position":3,"is_corresponding":false},{"id":622325,"name":"Savitha Sridharan","orcid":null,"position":4,"is_corresponding":false},{"id":620870,"name":"Jonathan Remis","orcid":"0000-0001-8317-4513","position":5,"is_corresponding":false},{"id":310085,"name":"Daniel B. Toso","orcid":null,"position":6,"is_corresponding":false},{"id":277728,"name":"Abhay Kotecha","orcid":"0000-0002-4480-5439","position":7,"is_corresponding":false},{"id":575762,"name":"Diana M. Bautista","orcid":"0000-0002-6809-8951","position":8,"is_corresponding":false},{"id":620871,"name":"Stephen G. Brohawn","orcid":"0000-0001-6768-3406","position":9,"is_corresponding":false},{"id":620867,"name":"David M. Kern","orcid":"0000-0001-8529-9045","position":0,"is_corresponding":true}],"reference_count":127,"raw_metadata":null,"created_at":"2026-07-18T23:42:18.947086Z","pmid":"34158638","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":[]}