{"doi":"10.1038/s42003-025-08795-1","title":"A conserved mechanism of LRRC8 channel inhibition by two structurally distinct drugs","abstract":"Leucine Rich Repeat Containing 8 (LRRC8) anion channels are emerging therapeutic targets, but their pharmacology is poorly developed. We employed a structurally defined homomeric channel chimera (8C-8A(IL125)) and heteromeric LRRC8A/LRRC8C (8A/8C) channels to investigate the mechanism of action of two structurally distinct LRRC8 inhibitors: zafirlukast and pranlukast. Molecular dynamics simulations identified zafirlukast binding sites in 8C-8A(IL125) comprising the amino (N)-terminal domain (NTD) and inter-subunit fenestrae between transmembrane (TM) helices 1 and 2. Pranlukast also clusters in fenestrae albeit closer to the external pore. Patch clamp analysis revealed that mutations in NTD, TM1, and TM2 alter 8C-8A(IL125) and 8A/8C sensitivity to zafirlukast and pranlukast, suggesting a common mechanism. The association between voltage-dependent inactivation induced by mutations or low pH and inhibitor sensitivity suggests that drug inhibition involves disruption of protein-lipid interactions and destabilization of the pore. This may represent a common mechanism of LRRC8 channel inhibition by lipophilic drugs. Molecular modeling and functional mutagenesis analysis identify a novel mechanism of LRRC8 volume-regulated anion channel inhibition by structurally distinct lipophilic drugs","journal":"Communications Biology","year":2025,"id":532987,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9613,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":403046,"name":"Paola Bisignano","orcid":"0000-0003-1789-762X","position":1,"is_corresponding":false},{"id":467089,"name":"Erkan Karakaş","orcid":"0000-0001-6552-3185","position":2,"is_corresponding":false},{"id":328000,"name":"Jerod S. Denton","orcid":"0000-0003-0032-8586","position":3,"is_corresponding":false},{"id":992747,"name":"Toshiki Yamada","orcid":"0000-0001-5808-2625","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":null,"created_at":"2026-07-19T02:51:27.893975Z","pmid":"41053296","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":[]}