{"doi":"10.1016/j.jbc.2024.108109","title":"Mechanistic insights into the selective targeting of P2X3 receptor by camlipixant antagonist","abstract":"ATP-activated P2X3 receptors play a pivotal role in chronic cough, affecting more than 10% of the population. Despite the challenges posed by the highly conserved structure of P2X receptors, efforts to develop selective drugs targeting P2X3 have led to the development of camlipixant, a potent, selective P2X3 antagonist. However, the mechanisms of receptor desensitization, ion permeation, and structural basis of camlipixant binding to P2X3 remain unclear. Here, we report a cryo-EM structure of camlipixant-bound P2X3, revealing a previously undiscovered selective drug-binding site in the receptor. Our findings also demonstrate that conformational changes in the upper body domain, including the turret and camlipixant-binding pocket, play a critical role: turret opening facilitates P2X3 channel closure to a radius of 0.7 Å, hindering cation transfer, whereas turret closure leads to channel opening. Structural and functional studies combined with molecular dynamics simulations provide a comprehensive understanding of camlipixant's selective inhibition of P2X3, offering a foundation for future drug development targeting this receptor.","journal":"Journal of Biological Chemistry","year":2024,"id":429313,"datarank":0.41188938021240973,"base_score":2.3978952727983707,"endowment":2.3978952727983707,"self_citation_contribution":0.3596842909197557,"citation_network_contribution":0.05220508929265408,"self_endowment_contribution":0.3596842909197557,"citer_contribution":0.05220508929265408,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":10,"citers_with_citation_signal":4,"citers_with_endowment":4,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9509,"is_data_producer":true,"deposit_databanks":{"ClinicalTrials.gov":["NCT05599191"]},"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":1144310,"name":"KanagaVijayan Dhanabalan","orcid":"0000-0001-8636-2616","position":1,"is_corresponding":false},{"id":1231419,"name":"Prajwal P. Nandekar","orcid":"0000-0003-0210-9301","position":2,"is_corresponding":false},{"id":1231952,"name":"S.C. Stauffer","orcid":null,"position":3,"is_corresponding":false},{"id":290676,"name":"Iring Heisler","orcid":null,"position":4,"is_corresponding":false},{"id":802142,"name":"Sarah Alvarado","orcid":"0000-0002-5653-1578","position":5,"is_corresponding":false},{"id":1231953,"name":"J Snyder","orcid":null,"position":6,"is_corresponding":false},{"id":369406,"name":"S. Ramaswamy","orcid":"0000-0002-6709-190X","position":7,"is_corresponding":false},{"id":1231418,"name":"Trung Thanh Thach","orcid":"0000-0001-8395-0623","position":0,"is_corresponding":true}],"reference_count":34,"raw_metadata":null,"created_at":"2026-07-19T01:59:06.668462Z","pmid":"39706278","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":[]}