{"doi":"10.7554/elife.103159","title":"AI-based discovery and cryoEM structural elucidation of a KATP channel pharmacochaperone","abstract":"Pancreatic K ATP channel trafficking defects underlie congenital hyperinsulinism (CHI) cases unresponsive to the K ATP channel opener diazoxide, the mainstay medical therapy for CHI. Current clinically used K ATP channel inhibitors have been shown to act as pharmacochaperones and restore surface expression of trafficking mutants; however, their therapeutic utility for K ATP trafficking-impaired CHI is hindered by high affinity binding, which limits functional recovery of rescued channels. Recent structural studies of K ATP channels employing cryo-electron microscopy (cryoEM) have revealed a promiscuous pocket where several known K ATP pharmacochaperones bind. The structural knowledge provides a framework for discovering K ATP channel pharmacochaperones with desired reversible inhibitory effects to permit functional recovery of rescued channels. Using an AI-based virtual screening technology AtomNet followed by functional validation, we identified a novel compound, termed Aekatperone, which exhibits chaperoning effects on K ATP channel trafficking mutations. Aekatperone reversibly inhibits K ATP channel activity with a half-maximal inhibitory concentration (IC 50 ) ~9 μM. Mutant channels rescued to the cell surface by Aekatperone showed functional recovery upon washout of the compound. CryoEM structure of K ATP bound to Aekatperone revealed distinct binding features compared to known high affinity inhibitor pharmacochaperones. Our findings unveil a K ATP pharmacochaperone enabling functional recovery of rescued channels as a promising therapeutic for CHI caused by K ATP trafficking defects.","journal":"eLife","year":2024,"id":487562,"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":0.951,"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":663174,"name":"Camden Driggers","orcid":"0000-0002-2105-7175","position":1,"is_corresponding":false},{"id":1331899,"name":"Ha H. Truong","orcid":"0000-0002-2322-378X","position":2,"is_corresponding":false},{"id":1331900,"name":"Zhongying Yang","orcid":"0000-0003-4686-0869","position":3,"is_corresponding":false},{"id":1331901,"name":"John F. Allen","orcid":"0000-0002-0950-0429","position":4,"is_corresponding":false},{"id":263936,"name":"Niel M. Henriksen","orcid":"0000-0002-7916-0757","position":5,"is_corresponding":false},{"id":832331,"name":"Katarzyna Walczewska-Szewc","orcid":"0000-0001-6422-6138","position":6,"is_corresponding":false},{"id":397234,"name":"Show‐Ling Shyng","orcid":"0000-0002-8230-8820","position":7,"is_corresponding":false},{"id":397232,"name":"Assmaa ElSheikh","orcid":"0000-0001-7360-9309","position":0,"is_corresponding":true}],"reference_count":88,"raw_metadata":null,"created_at":"2026-07-19T02:08:10.215754Z","pmid":"40135739","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":[]}