{"doi":"10.1101/2020.03.30.016154","title":"High-resolution Structures of multiple 5-HT <sub>3A</sub> R-setron complexes reveal a novel mechanism of competitive inhibition","abstract":"Abstract Serotonin receptors (5-HT 3A R) play a crucial role in regulating gut movement, and are the principal target of setrons, a class of high-affinity competitive antagonists, used in the management of nausea and vomiting associated with radiation and chemotherapies. Structural insights into setron-binding poses and their inhibitory mechanisms are just beginning to emerge. Here, we present high-resolution cryo-EM structures of full-length 5-HT 3A R in complex with palonosetron, ondansetron, and alosetron. Each structure reveals a distinct interaction fingerprint between the setron and binding-pocket residues that may underlie their diverse affinities. In addition, setrons elicit varying degrees of conformational change throughout the channel that, quite surprisingly, lie along the channel activation pathway, suggesting a novel mechanism of competitive inhibition. Molecular dynamic simulations were used to assess binding-poses and the drug-target interaction dynamics. Together, this study provides a molecular basis for setron binding affinities and their inhibitory effects.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":129280,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9517,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":271121,"name":"Arvind Kumar","orcid":"0000-0002-8421-8669","position":1,"is_corresponding":false},{"id":328773,"name":"Steven Ramsey","orcid":"0000-0001-7441-3228","position":2,"is_corresponding":false},{"id":328774,"name":"Eric Gibbs","orcid":"0000-0001-9073-9893","position":3,"is_corresponding":false},{"id":328775,"name":"Abhijeet Kapoor","orcid":"0000-0002-3606-3463","position":4,"is_corresponding":false},{"id":328776,"name":"Marta Filizola","orcid":"0000-0002-4382-8276","position":5,"is_corresponding":false},{"id":271127,"name":"Sudha Chakrapani","orcid":"0000-0003-0722-2338","position":6,"is_corresponding":false},{"id":271122,"name":"Sandip Basak","orcid":"0000-0003-4018-8020","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-18T23:15:45.920615Z","pmid":null,"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":[]}