2. Academic Validation
  3. Structure basis for the activation of KCNQ2 by endogenous and exogenous ligands

Structure basis for the activation of KCNQ2 by endogenous and exogenous ligands

  • Cell Rep. 2026 Jan 27;45(1):116771. doi: 10.1016/j.celrep.2025.116771.
Yiwen Zhao 1,  Zhenni Yang 2,  Sai Shi 3,  Han Hao 1,  Xinmeng Li 1,  Demin Ma 4,  Nannan Su 5,  Weixin Zhao 1,  Jicheng Shao 6,  Yating An 1,  Ke Wang 1,  Yinuo Liu 1,  Lu Zou 1,  Jinlong Qi 6,  Hailin Zhang 1,  Jiangtao Guo 7,  Xiaona Du 8
Affiliations

Affiliations

  • 1 Department of Pharmacology, Hebei Medical University, The Key Laboratory of New Drug Pharmacology and Toxicology of Hebei Province, The Collaboration Innovation Center for Mechanism, Diagnosis and Treatment of Neurological and Psychiatric Disease of Hebei Province, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang 050017, China.
  • 2 Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Department of Physiology, Shanxi Medical University, Taiyuan 030001, China; The Fifth Clinical Medical College of Shanxi Medical University, Department of Neurology, Shanxi Provincial People's Hospital, Shanxi Key Laboratory of Brain Disease Control, Taiyuan 030012, China; Department of Biophysics and Department of Neurology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China; Nanhu Brain-computer Interface Institute, Hangzhou, Zhejiang 311100, China.
  • 3 Department of Medical and Pharmaceutical Informatics, Hebei Medical University, Shijiazhuang 050017, China.
  • 4 Department of Biophysics and Department of Neurology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China; Nanhu Brain-computer Interface Institute, Hangzhou, Zhejiang 311100, China.
  • 5 Center for Membrane Receptors and Brain Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, Zhejiang 322000, China.
  • 6 Department of Pharmacology, Hebei Medical University, The Key Laboratory of New Drug Pharmacology and Toxicology of Hebei Province, The Collaboration Innovation Center for Mechanism, Diagnosis and Treatment of Neurological and Psychiatric Disease of Hebei Province, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang 050017, China; Department of Core Facilities and Centers, Hebei Medical University, Shijiazhuang 050017, China.
  • 7 Department of Biophysics and Department of Neurology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China; Nanhu Brain-computer Interface Institute, Hangzhou, Zhejiang 311100, China. Electronic address: [email protected].
  • 8 Department of Pharmacology, Hebei Medical University, The Key Laboratory of New Drug Pharmacology and Toxicology of Hebei Province, The Collaboration Innovation Center for Mechanism, Diagnosis and Treatment of Neurological and Psychiatric Disease of Hebei Province, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang 050017, China. Electronic address: [email protected].
PMID: 41442279 DOI: 10.1016/j.celrep.2025.116771
Abstract

The voltage-gated Potassium Channel KCNQ2 is crucial for stabilizing neuronal membrane potential, and its mutations can cause various epilepsies. KCNQ2 is activated by endogenous ligand phosphatidylinositol-4,5-bisphosphate (PIP2) and exogenous ligands, yet the structural mechanisms underlying these activations remain unclear. Here, we report the cryo-electron microscopy structures of human KCNQ2 in complex with exogenous ligands QO-58 and QO-83 in the absence or presence of PIP2 in either closed or open conformation. While QO-83 binds in the classical fenestration pocket of the pore domain, QO-58 mainly binds at the flank of S4 in the voltage-sensing domain. These structures, along with electrophysiological assays and computational studies, provide mechanistic insights into the ligand activation of KCNQ2 and may guide the development of anti-epileptic drugs targeting KCNQ2.

Keywords

CP: molecular biology; CP: neuroscience; KCNQ2; PIP(2); QO-58; QO-83; cryo-EM sructure; mechanism of ligand actvation.

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