{"doi":"10.1126/sciadv.adk4855","title":"Structural insights into the unexpected agonism of tetracyclic antidepressants at serotonin receptors 5-HT <sub>1e</sub> R and 5-HT <sub>1F</sub> R","abstract":"Serotonin [5-hydroxytryptamine (5-HT)] acts via 13 different receptors in humans. Of these receptor subtypes, all but 5-HT 1e R have confirmed roles in native tissue and are validated drug targets. Despite 5-HT 1e R’s therapeutic potential and plausible druggability, the mechanisms of its activation remain elusive. To illuminate 5-HT 1e R’s pharmacology in relation to the highly homologous 5-HT 1F R, we screened a library of aminergic receptor ligands at both receptors and observe 5-HT 1e R/5-HT 1F R agonism by multicyclic drugs described as pan-antagonists at 5-HT receptors. Potent agonism by tetracyclic antidepressants mianserin, setiptiline, and mirtazapine suggests a mechanism for their clinically observed antimigraine properties. Using cryo-EM and mutagenesis studies, we uncover and characterize unique agonist-like binding poses of mianserin and setiptiline at 5-HT 1e R distinct from similar drug scaffolds in inactive-state 5-HTR structures. Together with computational studies, our data suggest that these binding poses alongside receptor-specific allosteric coupling in 5-HT 1e R and 5-HT 1F R contribute to the agonist activity of these antidepressants.","journal":"Science Advances","year":2024,"id":454397,"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":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9586,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1191267,"name":"Alexandra Kalia Parpounas","orcid":"0009-0002-5837-4518","position":1,"is_corresponding":false},{"id":1191268,"name":"Audrey L. Warren","orcid":"0000-0002-1538-8648","position":2,"is_corresponding":false},{"id":920923,"name":"Bianca Fiorillo","orcid":"0000-0002-3025-5157","position":3,"is_corresponding":false},{"id":352614,"name":"Davide Provasi","orcid":"0000-0002-2868-303X","position":4,"is_corresponding":false},{"id":328776,"name":"Marta Filizola","orcid":"0000-0002-4382-8276","position":5,"is_corresponding":false},{"id":226972,"name":"Daniel Wacker","orcid":"0000-0003-4951-7230","position":6,"is_corresponding":false},{"id":988490,"name":"Gregory Zilberg","orcid":"0000-0002-6575-508X","position":0,"is_corresponding":true}],"reference_count":77,"raw_metadata":null,"created_at":"2026-07-19T02:03:07.923686Z","pmid":"38630816","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":[]}