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Secondary structure transitions and dual PIP2 binding define cardiac KCNQ1-KCNE1 channel gating

Ling Zhong^1,† , Xiaoqing Lin^1,† , Xinyu Cheng^2,3,† , Shuangyan Wan^2,3,† , Yaoguang Hua^2,3 , Weiwei Nan^2,3 , Bin Hu⁴ , Xiangjun Peng⁵ , Zihan Zhou⁶ , Qiansen Zhang⁶ , Huaiyu Yang⁶ , Frank Noé⁷ , Zhenzhen Yan¹ , Dexiang Jiang¹ , Hangyu Zhang¹ , Fengjiao Liu¹ , Chenxin Xiao¹ , Zhuo Zhou¹ , Yimin Mou¹ , Haijie Yu¹ , Lijuan Ma¹ , Chen Huang¹ , Vincent Kam Wai Wong^1,8 , Sookja Kim Chung^1,9 , Bing Shen^1,8 , Zhi-Hong Jiang^1,8 , Erwin Neher^1,8 , Wandi Zhu¹⁰ , Jin Zhang^2,3,* , Panpan Hou^1,8,*

¹Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery; State Key Laboratory of Mechanism and Quality of Chinese Medicine & School of Pharmacy, Faculty of Medicine; Faculty of Chinese Medicine, Macau University of Science and Technology, Macau SAR, China
²The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
³Jiangxi Provincial Key Laboratory of Tumor Biology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
⁴School of Basic Medical Sciences, Gannan Medical University, Ganzhou, Jiangxi, China
⁵Department of Engineering Mechanics, Applied Mechanics Laboratory, Institute of Biomechanics and Medical Engineering, Tsinghua University, Beijing, China
⁶Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
⁷Department of Mathematics and Informatics, Freie Universität Berlin, Berlin, Germany
⁸Macau University of Science and Technology Innovation Technology Research Institute, Hengqin, Guangdong, China
⁹State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China
¹⁰College of Medicine, Department of Molecular Medicine and Therapeutics, The Ohio State University. Columbus, OH, USA
^†These authors contributed equally: Ling Zhong, Xiaoqing Lin, Xinyu Cheng, Shuangyan Wan
* Correspondence: Jin Zhang(zhangxiaokong@hotmail.com)Panpan Hou(pphou@must.edu.mo)

The KCNQ1 + KCNE1 potassium channel complex produces the slow delayed rectifier current (IKs) 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 KCNQ1APO, 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 linker, maintaining a loop conformation during IKs gating, while the other three, in S6 and helix A, undergo dynamic helix-loop transitions during IKs gating. These structural rearrangements: (1) stabilize the closed pore and the conformation of the intermediate state voltage-sensing domain, thereby determining channel gating, ion permeation, and single-channel conductance; (2) enable a dual-PIP2 modulation mechanism, where one PIP2 occupies the canonical site, while the second PIP2 bridges the S4–S5 linker, KCNE1, and the adjacent S6’, stabilizing channel opening; (3) create a fenestration capable of binding compounds specific for KCNQ1 + KCNE1 (e.g., AC-1). Together, these findings reveal a previously unrecognized large-scale secondary structural transition during ion channel gating that fine-tunes IKs function and provides a foundation for developing targeted LQTS therapy.

https://doi.org/10.1038/s41422-025-01182-9

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