{"doi":"10.1101/2024.06.26.600491","title":"Structure of the human K <sub>2P</sub> 13.1(THIK-1) channel reveals a novel hydrophilic pore restriction and lipid cofactor site","abstract":"The halothane-inhibited K 2P leak potassium channel K 2P 13.1 (THIK-1) 1–3 is found in diverse cells 1,4 including neurons 1,5 and microglia 6–8 where it affects surveillance 6 , synaptic pruning 7 , phagocytosis 7 , and inflammasome-mediated interleukin-1β release 6,8,9 . As with many K 2P s 1,5,10–14 and other voltage-gated ion channel (VGIC) superfamily members 3,15,16 , polyunsaturated fatty acid (PUFA) lipids modulate K 2P 13.1 (THIK-1) 1,5,14,17 via a poorly understood mechanism. Here, we present cryo-electronmicroscopy (cryo-EM) structures of human K 2P 13.1 (THIK-1) and mutants in lipid nanodiscs and detergent. These reveal that, unlike other K 2P s 13,18–24 , K 2P 13.1 (THIK-1) has a two-chamber aqueous inner cavity obstructed by a M4 transmembrane helix tyrosine (Tyr273, the flow restrictor). This hydrophilic barrier can be opened by an activatory mutation, S136P 25 , at natural break in the M2 transmembrane helix and by intrinsic channel dynamics. The structures also reveal a buried lipid in the P1/M4 intersubunit interface at a location, the PUFA site, that coincides with the TREK subfamily K 2P modulator pocket for small molecule agonists 18,26,27 . This overlap, together with the effects of mutation on K 2P 13.1 (THIK-1) PUFA responses, indicates that the PUFA site lipids are K 2P 13.1 (THIK-1) cofactors. Comparison with the PUFA-responsive VGIC Kv7.1 (KCNQ1) 28–31 reveals a shared role for the equivalent pore domain intersubunit interface in lipid modulation, providing a framework for dissecting the effects of PUFAs on the VGIC superfamily. Our findings reveal the unique architecture underlying K 2P 13.1 (THIK-1) function, highlight the importance of the P1/M4 interface in control of K 2P s by both natural and synthetic agents, and should aid development of THIK subfamily modulators for diseases such as neuroinflammation 6,32 and autism 6 .","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":485189,"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":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9655,"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":1022648,"name":"Seil Jang","orcid":"0009-0000-6816-5635","position":1,"is_corresponding":false},{"id":283879,"name":"Fayal Abderemane-Ali","orcid":null,"position":2,"is_corresponding":false},{"id":344234,"name":"Fiona B. Naughton","orcid":"0000-0003-0162-1346","position":3,"is_corresponding":false},{"id":283122,"name":"Michael Grabe","orcid":"0000-0003-3509-5997","position":4,"is_corresponding":false},{"id":283123,"name":"Daniel L. Minor","orcid":"0000-0002-5998-4214","position":5,"is_corresponding":false},{"id":1328216,"name":"Shatabdi Roy-Chowdhury","orcid":null,"position":0,"is_corresponding":true}],"reference_count":105,"raw_metadata":null,"created_at":"2026-07-19T02:07:47.633574Z","pmid":"38979306","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":[]}