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Phrixotoxin-3 binds to three distinct antagonistic sites on human Nav1.6

Cell Research volume 35, pages 610–613 (2025)Cite this article

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Dear Editor,

Voltage-gated sodium (Nav) channels govern the membrane excitability of neurons and muscles by mediating the rapid influx of Na+ ions in response to membrane depolarization.1 These functions are driven by the core Nav structure, which consists of a central pore domain (PD) and four surrounding voltage-sensing domains (VSDs).1 Among the nine human Nav subtypes (Nav1.1–1.9), Nav1.6, encoded by the SCN8A gene, is widely expressed in nervous systems, with particularly high density at the distal axon initial segment.2

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Fig. 1: PaurTx3 binds to three distinct sites on Nav1.6.

Data availability

The data that support this study are available from the corresponding authors upon reasonable request. The cryo-EM maps have been deposited in the Electron Microscopy Data Bank (EMDB) under accession code EMD-46943. The coordinates have been deposited in the Protein Data Bank (PDB) under accession code 9DK5.

References

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Acknowledgements

We thank the cryo-EM facility at Princeton Imaging and Analysis Center. This work is supported by the National Natural Science Foundation of China (32330052). X.F. has been supported by the HFSP long-term fellowship (LT000754/2020-L) from the International Human Frontier Science Program Organization (HFSPO). J.H. is supported by the start-up funding from Shenzhen Medical Academy of Research and Translation (SMART).

Author information

Author notes

  1. Xiao Fan

    Present address: Laboratory of Neurophysiology and Behavior, The Rockefeller University, New York, NY, USA

  2. These authors contributed equally: Xiao Fan, Jiaofeng Chen.

Authors and Affiliations

  1. Department of Molecular Biology, Princeton University, Princeton, NJ, USA

    Xiao Fan

  2. Beijing Frontier Research Center for Biological Structures, State Key Laboratory of Membrane Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China

    Jiaofeng Chen & Nieng Yan

  3. Institute of Bio-Architecture and Bio-Interactions (IBABI), Shenzhen Medical Academy of Research and Translation, Guangming District, Shenzhen, Guangdong, China

    Xiaoshuang Huang, Yuzhen Xie, Nieng Yan & Jian Huang

  4. State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, China

    Zhanfeng Hou & Zigang Li

  5. Pingshan Translational Medicine Center, Shenzhen Bay Laboratory, Shenzhen, Guangdong, China

    Zigang Li

  6. Institute of Chemical Biology, Shenzhen Bay Laboratory, Guangming District, Shenzhen, Guangdong, China

    Nieng Yan

Authors
  1. Xiao Fan
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  2. Jiaofeng Chen
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Contributions

N.Y., J.H. and X.F. conceived the project. X.F., J.C., X.H., Z.H., Y.X., Z.L., N.Y. and J.H. designed experiments; X.F. and J.H. performed all experiments related to cryo-EM studies, including protein expression and purification; Z.H. conducted experiments related to peptide toxin synthesis; X.H. and Y.X. prepared clones for electrophysiology; J.C. carried out experiments related to electrophysiology; X.F., J.C., X.H., Z.H., Y.X., Z.L., N.Y. and J.H. analyzed data; X.F., J.H. and N.Y. wrote the manuscript with input from all authors. All authors approved the final manuscript.

Corresponding authors

Correspondence to Nieng Yan or Jian Huang.

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The authors declare no competing interests.

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Fan, X., Chen, J., Huang, X. et al. Phrixotoxin-3 binds to three distinct antagonistic sites on human Nav1.6. Cell Res 35, 610–613 (2025). https://doi.org/10.1038/s41422-025-01141-4

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