2. Academic Validation
  3. Structural basis for modulation of human NaV1.3 by clinical drug and selective antagonist

Structural basis for modulation of human NaV1.3 by clinical drug and selective antagonist

  • Nat Commun. 2022 Mar 11;13(1):1286. doi: 10.1038/s41467-022-28808-5.
Xiaojing Li # 1 2 3,  Feng Xu # 4 5 6 7,  Hao Xu # 2 8,  Shuli Zhang 3 4,  Yiwei Gao 2 3,  Hongwei Zhang 2 3,  Yanli Dong 2,  Yanchun Zheng 3 4,  Bei Yang 2,  Jianyuan Sun 3 4 5 6,  Xuejun Cai Zhang 2 3,  Yan Zhao 9 10 11,  Daohua Jiang 12
Affiliations

Affiliations

  • 1 Laboratory of Soft Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing, 100190, China.
  • 2 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
  • 3 College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 4 State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing, 100101, China.
  • 5 Sino-Danish College, University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 6 The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences (CAS), Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, 518055, China.
  • 7 Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen N, Denmark.
  • 8 Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China.
  • 9 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. [email protected].
  • 10 College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
  • 11 State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing, 100101, China. [email protected].
  • 12 Laboratory of Soft Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing, 100190, China. [email protected].
  • # Contributed equally.
PMID: 35277491 DOI: 10.1038/s41467-022-28808-5
Abstract

Voltage-gated sodium (NaV) channels play fundamental roles in initiating and propagating action potentials. NaV1.3 is involved in numerous physiological processes including neuronal development, hormone secretion and pain perception. Here we report structures of human NaV1.3/β1/β2 in complex with clinically-used drug bulleyaconitine A and selective antagonist ICA121431. Bulleyaconitine A is located around domain I-II fenestration, providing the detailed view of the site-2 neurotoxin binding site. It partially blocks ion path and expands the pore-lining helices, elucidating how the bulleyaconitine A reduces peak amplitude but improves channel open probability. In contrast, ICA121431 preferentially binds to activated domain IV voltage-sensor, consequently strengthens the Ile-Phe-Met motif binding to its receptor site, stabilizes the channel in inactivated state, revealing an allosterically inhibitory mechanism of NaV channels. Our results provide structural details of distinct small-molecular modulators binding sites, elucidate molecular mechanisms of their action on NaV channels and pave a way for subtype-selective therapeutic development.

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