Ligand activation mechanisms of human KCNQ2 channel

Demin Ma; Yueming Zheng; Xiaoxiao Li; Xiaoyu Zhou; Zhenni Yang; Yan Zhang; Long Wang; Wenbo Zhang; Jiajia Fang; Guohua Zhao; Panpan Hou; Fajun Nan; Wei Yang; Nannan Su; Zhaobing Gao; Jiangtao Guo

doi:10.1038/s41467-023-42416-x

Nature Communications (Oct 2023)

Affiliations

Demin Ma: Department of Biophysics and Department of Neurology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine
Yueming Zheng: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Xiaoxiao Li: Department of Biophysics and Department of Neurology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine
Xiaoyu Zhou: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Zhenni Yang: Department of Biophysics and Department of Neurology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine
Yan Zhang: Department of Biophysics and Department of Neurology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine
Long Wang: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Wenbo Zhang: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Jiajia Fang: Department of Neurology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine
Guohua Zhao: Department of Neurology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine
Panpan Hou: Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology
Fajun Nan: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Wei Yang: Department of Biophysics and Department of Neurology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine
Nannan Su: Department of Biophysics and Department of Neurology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine
Zhaobing Gao: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Jiangtao Guo: Department of Biophysics and Department of Neurology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine

DOI: https://doi.org/10.1038/s41467-023-42416-x
Journal volume & issue: Vol. 14, no. 1
pp. 1 – 13

Abstract

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Abstract The human voltage-gated potassium channel KCNQ2/KCNQ3 carries the neuronal M-current, which helps to stabilize the membrane potential. KCNQ2 can be activated by analgesics and antiepileptic drugs but their activation mechanisms remain unclear. Here we report cryo-electron microscopy (cryo-EM) structures of human KCNQ2-CaM in complex with three activators, namely the antiepileptic drug cannabidiol (CBD), the lipid phosphatidylinositol 4,5-bisphosphate (PIP2), and HN37 (pynegabine), an antiepileptic drug in the clinical trial, in an either closed or open conformation. The activator-bound structures, along with electrophysiology analyses, reveal the binding modes of two CBD, one PIP2, and two HN37 molecules in each KCNQ2 subunit, and elucidate their activation mechanisms on the KCNQ2 channel. These structures may guide the development of antiepileptic drugs and analgesics that target KCNQ2.

Published in Nature Communications

ISSN: 2041-1723 (Online)
Publisher: Nature Portfolio
Country of publisher: United Kingdom
LCC subjects: Science
Website: https://www.nature.com/ncomms/

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