A small-molecule activation mechanism that directly opens the KCNQ2 channel

  • Nat Chem Biol. 2024 Jan 2. doi: 10.1038/s41589-023-01515-y.
Shaoying Zhang  #  1 ,  Demin Ma  #  2 ,  Kun Wang  #  1 ,  Ya Li  #  1 ,  Zhenni Yang  2 ,  Xiaoxiao Li  2 ,  Junnan Li  1 ,  Jiangnan He  1 ,  Lianghe Mei  3 ,  Yangliang Ye  3 ,  Zongsheng Chen  4 ,  Juwen Shen  1 ,  Panpan Hou  5 ,  Jiangtao Guo  6 ,  Qiansen Zhang  7 ,  Huaiyu Yang  8
Affiliations
  • 1. Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
  • 2. Department of Biophysics, and Department of Neurology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 3. Suzhou Institute of Drug Innovation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Suzhou, China.
  • 4. Department of Neurology, Wuhu Hospital Affiliated to East China Normal University, Wuhu, China.
  • 5. Dr Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao SAR, China.
  • 6. Department of Biophysics, and Department of Neurology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • 7. Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China. [email protected].
  • 8. Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 38167918 DOI: 10.1038/s41589-023-01515-y
Abstract

Pharmacological activation of voltage-gated ion channels by ligands serves as the basis for therapy and mainly involves a classic gating mechanism that augments the native voltage-dependent open probability. Through structure-based virtual screening, we identified a new scaffold compound, Ebio1, serving as a potent and subtype-selective activator for the voltage-gated Potassium Channel KCNQ2 and featuring a new activation mechanism. Single-channel patch-clamp, cryogenic-electron microscopy and molecular dynamic simulations, along with chemical derivatives, reveal that Ebio1 engages the KCNQ2 activation by generating an extended channel gate with a larger conductance at the saturating voltage (+50 mV). This mechanism is different from the previously observed activation mechanism of ligands on voltage-gated ion channels. Ebio1 caused S6 helices from residues S303 and F305 to perform a twist-to-open movement, which was sufficient to open the KCNQ2 gate. Overall, our findings provide mechanistic insights into the activation of KCNQ2 channel by Ebio1 and lend support for KCNQ-related drug development.

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