{"doi":"10.1101/2023.08.01.551546","title":"Structure of an open K <sub>ATP</sub> channel reveals tandem PIP <sub>2</sub> binding sites mediating the Kir6.2 and SUR1 regulatory interface","abstract":"Abstract ATP-sensitive potassium (K ATP ) channels, composed of four pore-lining Kir6.2 subunits and four regulatory sulfonylurea receptor 1 (SUR1) subunits, control insulin secretion in pancreatic β-cells. K ATP channel opening is stimulated by PIP 2 and inhibited by ATP. Mutations that increase channel opening by PIP 2 reduce ATP inhibition and cause neonatal diabetes. Although considerable evidence has implicated a role for PIP 2 in K ATP channel function, previously solved open-channel structures have lacked bound PIP 2 , and mechanisms by which PIP 2 regulates K ATP channels remain unresolved. Here, we report cryoEM structure of a K ATP channel harboring the neonatal diabetes mutation Kir6.2-Q52R, bound to natural C18:0/C20:4 long-chain PI(4,5)P 2 in open conformation. The structure reveals two adjacent PIP 2 molecules between SUR1 and Kir6.2. The first PIP 2 binding site is conserved among PIP 2 -gated Kir channels. The second site forms uniquely in K ATP at the interface of Kir6.2 and SUR1. Functional studies demonstrate both binding sites determine channel activity. Kir6.2 pore opening is associated with a twist of the Kir6.2 cytoplasmic domain and a rotation of the N-terminal transmembrane domain of SUR1, which widens the inhibitory ATP binding pocket to disfavor ATP binding. The open conformation is particularly stabilized by the Kir6.2-Q52R residue through cation-π bonding with SUR1 - W51. Together, these results uncover the cooperation between SUR1 and Kir6.2 in PIP 2 binding and gating, explain the antagonistic regulation of K ATP channels by PIP 2 and ATP, and provide the mechanism by which Kir6.2-Q52R stabilizes an open channel to cause neonatal diabetes.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":392521,"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":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9486,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1166115,"name":"Yi‐Ying Kuo","orcid":"0000-0002-6876-8126","position":1,"is_corresponding":false},{"id":475806,"name":"Phillip Zhu","orcid":"0000-0002-9756-2637","position":2,"is_corresponding":false},{"id":397232,"name":"Assmaa ElSheikh","orcid":"0000-0001-7360-9309","position":3,"is_corresponding":false},{"id":397234,"name":"Show‐Ling Shyng","orcid":"0000-0002-8230-8820","position":4,"is_corresponding":false},{"id":663174,"name":"Camden Driggers","orcid":"0000-0002-2105-7175","position":0,"is_corresponding":true}],"reference_count":67,"raw_metadata":null,"created_at":"2026-07-19T01:18:56.730121Z","pmid":"37577494","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":[]}