{"doi":"10.1016/j.cell.2024.01.032","title":"Structural mechanisms of α7 nicotinic receptor allosteric modulation and activation","abstract":"The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel that plays an important role in cholinergic signaling throughout the nervous system. Its unique physiological characteristics and implications in neurological disorders and inflammation make it a promising but challenging therapeutic target. Positive allosteric modulators overcome limitations of traditional α7 agonists, but their potentiation mechanisms remain unclear. Here, we present high-resolution structures of α7-modulator complexes, revealing partially overlapping binding sites but varying conformational states. Structure-guided functional and computational tests suggest that differences in modulator activity arise from the stable rotation of a channel gating residue out of the pore. We extend the study using a time-resolved cryoelectron microscopy (cryo-EM) approach to reveal asymmetric state transitions for this homomeric channel and also find that a modulator with allosteric agonist activity exploits a distinct channel-gating mechanism. These results define mechanisms of α7 allosteric modulation and activation with implications across the pentameric receptor superfamily.","journal":"Cell","year":2024,"id":417938,"datarank":1.0574577511920555,"base_score":4.07753744390572,"endowment":4.07753744390572,"self_citation_contribution":0.611630616585858,"citation_network_contribution":0.4458271346061974,"self_endowment_contribution":0.611630616585858,"citer_contribution":0.4458271346061974,"corpus_percentile":null,"corpus_rank":null,"citation_count":58,"citer_count":52,"citers_with_citation_signal":29,"citers_with_endowment":29,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9595,"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":1205204,"name":"Mariia Avstrikova","orcid":null,"position":1,"is_corresponding":false},{"id":230422,"name":"Colleen Noviello","orcid":"0000-0002-0055-1019","position":2,"is_corresponding":false},{"id":400605,"name":"Nuriya Mukhtasimova","orcid":"0000-0001-6652-1974","position":3,"is_corresponding":false},{"id":77841,"name":"Jean‐Pierre Changeux","orcid":"0000-0003-0297-1583","position":4,"is_corresponding":false},{"id":402358,"name":"Ganesh A. Thakur","orcid":"0000-0001-8228-5799","position":5,"is_corresponding":false},{"id":341481,"name":"Steven M. Sine","orcid":"0000-0002-0594-6052","position":6,"is_corresponding":false},{"id":1204584,"name":"Marco Cecchini","orcid":"0000-0003-2671-1583","position":7,"is_corresponding":false},{"id":230423,"name":"Ryan Hibbs","orcid":"0000-0003-4283-1147","position":8,"is_corresponding":false},{"id":909959,"name":"Sean M. Burke","orcid":null,"position":0,"is_corresponding":true}],"reference_count":132,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:56:56.807779Z","pmid":"38382524","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":[]}