{"doi":"10.17615/yb2v-ca64","title":"Structure of a Hallucinogen-Activated Gq-Coupled 5-HT2A Serotonin Receptor","abstract":"Hallucinogens like lysergic acid diethylamide (LSD), psilocybin, and substituted N-benzyl phenylalkylamines are widely used recreationally with psilocybin being considered as a therapeutic for many neuropsychiatric disorders including depression, anxiety, and substance abuse. How psychedelics mediate their actions—both therapeutic and hallucinogenic—are not understood, although activation of the 5-HT2A serotonin receptor (HTR2A) is key. To gain molecular insights into psychedelic actions, we determined the active-state structure of HTR2A bound to 25-CN-NBOH—a prototypical hallucinogen—in complex with an engineered Gαq heterotrimer by cryoelectron microscopy (cryo-EM). We also obtained the X-ray crystal structures of HTR2A complexed with the arrestin-biased ligand LSD or the inverse agonist methiothepin. Comparisons of these structures reveal determinants responsible for HTR2A-Gαq protein interactions as well as the conformational rearrangements involved in active-state transitions. Given the potential therapeutic actions of hallucinogens, these findings could accelerate the discovery of more selective drugs for the treatment of a variety of neuropsychiatric disorders. © 2020 Elsevier Inc.; Roth et al. reveal structurally how psychedelics, including LSD, psilocin, mescaline, and various N-BOH analogs, mediate their therapeutic and hallucinogenic effects by binding to and activating their molecular target, the serotonin (5-HT) 2A receptor coupled with G-protein Gαq.","journal":"UNC Libraries","year":2024,"id":499878,"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":0.9524,"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":1349342,"name":"Nichols D.E","orcid":null,"position":1,"is_corresponding":false},{"id":1348493,"name":"Shoichet B.K","orcid":null,"position":2,"is_corresponding":false},{"id":1349343,"name":"Lyu J","orcid":null,"position":3,"is_corresponding":false},{"id":226976,"name":"Georgios Skiniotis","orcid":"0000-0003-0238-7846","position":4,"is_corresponding":false},{"id":1348215,"name":"Che T","orcid":null,"position":5,"is_corresponding":false},{"id":1325042,"name":"Roth B.L","orcid":null,"position":6,"is_corresponding":false},{"id":1348221,"name":"DiBerto J.F","orcid":null,"position":7,"is_corresponding":false},{"id":226972,"name":"Daniel Wacker","orcid":"0000-0003-4951-7230","position":8,"is_corresponding":false},{"id":1348783,"name":"Robertson M.J","orcid":null,"position":9,"is_corresponding":false},{"id":406378,"name":"Kami Kim","orcid":"0000-0003-3384-152X","position":10,"is_corresponding":false},{"id":1348792,"name":"Krumm B.E","orcid":null,"position":11,"is_corresponding":false},{"id":1348781,"name":"Seven A.B","orcid":null,"position":12,"is_corresponding":false},{"id":226971,"name":"Ouliana Panova","orcid":"0000-0002-5089-620X","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:10:04.829419Z","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":[]}