{"doi":"10.1073/pnas.2109083119","title":"Structure of the human cation–chloride cotransport KCC1 in an outward-open state","abstract":"Cation–chloride cotransporters (CCCs) catalyze electroneutral symport of Cl − with Na + and/or K + across membranes. CCCs are fundamental in cell volume homeostasis, transepithelia ion movement, maintenance of intracellular Cl − concentration, and neuronal excitability. Here, we present a cryoelectron microscopy structure of human K + –Cl − cotransporter (KCC)1 bound with the VU0463271 inhibitor in an outward-open state. In contrast to many other amino acid–polyamine–organocation transporter cousins, our first outward-open CCC structure reveals that opening the KCC1 extracellular ion permeation path does not involve hinge-bending motions of the transmembrane (TM) 1 and TM6 half-helices. Instead, rocking of TM3 and TM8, together with displacements of TM4, TM9, and a conserved intracellular loop 1 helix, underlie alternate opening and closing of extracellular and cytoplasmic vestibules. We show that KCC1 intriguingly exists in one of two distinct dimeric states via different intersubunit interfaces. Our studies provide a blueprint for understanding the mechanisms of CCCs and their inhibition by small molecule compounds.","journal":"Proceedings of the National Academy of Sciences","year":2022,"id":250606,"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":26,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9478,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":297716,"name":"Jiemin Shen","orcid":"0000-0002-3977-0681","position":1,"is_corresponding":false},{"id":309659,"name":"Qinzhe Wang","orcid":null,"position":2,"is_corresponding":false},{"id":892786,"name":"Manuel José Ruiz Munevar","orcid":"0000-0003-0506-2684","position":3,"is_corresponding":false},{"id":310027,"name":"Pietro Vidossich","orcid":null,"position":4,"is_corresponding":false},{"id":308729,"name":"Marco De Vivo","orcid":"0000-0003-4022-5661","position":5,"is_corresponding":false},{"id":297721,"name":"Ming Zhou","orcid":"0000-0001-7198-165X","position":6,"is_corresponding":false},{"id":307402,"name":"Erhu Cao","orcid":"0000-0003-3102-5692","position":7,"is_corresponding":false},{"id":557079,"name":"Yongxiang Zhao","orcid":"0000-0001-8209-6015","position":0,"is_corresponding":true}],"reference_count":82,"raw_metadata":null,"created_at":"2026-07-19T00:24:32.960657Z","pmid":"35759661","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":[]}