biostudies-literatureZhong LMacau University of Science and Technology Foundation (MUST Foundation)National Natural Science Foundation of China (National Science Foundation of China)887-899https://www.ebi.ac.uk/biostudies/studies/S-EPMC12589563biostudies-literatureUnknown35(11)The KCNQ1 + KCNE1 potassium channel complex produces the slow delayed rectifier current (I_Ks) critical for cardiac repolarization. Loss-of-function mutations in KCNQ1 and KCNE1 cause long QT syndrome (LQTS) types 1 and 5 (LQT1/LQT5), accounting for over one-third of clinical LQTS cases. Despite prior structural work on KCNQ1 and KCNQ1 + KCNE3, the structural basis of KCNQ1 + KCNE1 remains unresolved. Using cryo-electron microscopy and electrophysiology, we determined high-resolution (2.5-3.4 Å) structures of human KCNQ1_APO, and KCNQ1 + KCNE1 in both closed and open states. KCNE1 occupies a pivotal position at the interface of three KCNQ1 subunits, inducing six helix-to-loop transitions in KCNQ1 transmembrane segments. Three of them occur at both ends of the S4-S5 linkCell researchSecondary structure transitions and dual PIP2 binding define cardiac KCNQ1-KCNE1 channel gating.PMC1258956332171221FRG-23-030-SKL32271260Wan SPeng XHuang CMa LZhang JZhang HLin XNan WShen BCheng XZhang QYu HYan ZChung SKWong VKWJiang ZHMou YHua YYang HNeher EHu BZhou ZHou PNoe FJiang DZhu WXiao CZhong LLiu FfalseSecondary structure transitions and dual PIP2 binding define cardiac KCNQ1-KCNE1 channel gating.The KCNQ1 + KCNE1 potassium channel complex produces the slow delayed rectifier current (I_Ks) critical for cardiac repolarization. Loss-of-function mutations in KCNQ1 and KCNE1 cause long QT syndrome (LQTS) types 1 and 5 (LQT1/LQT5), accounting for over one-third of clinical LQTS cases. Despite prior structural work on KCNQ1 and KCNQ1 + KCNE3, the structural basis of KCNQ1 + KCNE1 remains unresolved. Using cryo-electron microscopy and electrophysiology, we determined high-resolution (2.5-3.4 Å) structures of human KCNQ1_APO, and KCNQ1 + KCNE1 in both closed and open states. KCNE1 occupies a pivotal position at the interface of three KCNQ1 subunits, inducing six helix-to-loop transitions in KCNQ1 transmembrane segments. Three of them occur at both ends of the S4-S5 link2025-01-01T00:00:00Z2025 Nov2026-07-15T06:33:40.471Z2026-06-30T03:23:17.821ZS-EPMC125895634103462410.1038/s41422-025-01182-9