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

Xiaojing Li, Feng Xu, Hao Xu, Shuli Zhang, Yiwei Gao, Hongwei Zhang, Yanli Dong, Yanchun Zheng, Bei Yang, Jianyuan Sun, Xuejun Cai Zhang, Yan Zhao () and Daohua Jiang ()
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Xiaojing Li: Chinese Academy of Sciences
Feng Xu: Chinese Academy of Sciences
Hao Xu: Chinese Academy of Sciences
Shuli Zhang: University of Chinese Academy of Sciences
Yiwei Gao: Chinese Academy of Sciences
Hongwei Zhang: Chinese Academy of Sciences
Yanli Dong: Chinese Academy of Sciences
Yanchun Zheng: University of Chinese Academy of Sciences
Bei Yang: Chinese Academy of Sciences
Jianyuan Sun: University of Chinese Academy of Sciences
Xuejun Cai Zhang: Chinese Academy of Sciences
Yan Zhao: Chinese Academy of Sciences
Daohua Jiang: Chinese Academy of Sciences

Nature Communications, 2022, vol. 13, issue 1, 1-10

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28808-5

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