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

<div class='caption-title'>Functional characterization and overall structure of human NaV1.3/β1/β2.</div>
<div class='caption-title'>The binding site of BLA in NaV1.3.</div>
<div class='caption-title'>Structure basis for modulation of NaV1.3 by BLA.</div>
Li X, Xu F, Xu H, Zhang S, Gao Y, Zhang H, Dong Y, Zheng Y, Yang B, Sun J, Zhang XC, Zhao Y, Jiang D
OpenAccess logo Nat Commun 13 1286 (2022)
Cited: 29 times
EuropePMC logo PMID: 35277491

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.

Reviews - 7w77 mentioned but not cited (2)

  1. Structural Advances in Voltage-Gated Sodium Channels. Jiang D, Zhang J, Xia Z. Front Pharmacol 13 908867 (2022)
  2. A structural atlas of druggable sites on Nav channels. Li Z, Wu Q, Yan N. Channels (Austin) 18 2287832 (2024)

Articles - 7w77 mentioned but not cited (2)



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  2. Shining a Light on Venom-Peptide Receptors: Venom Peptides as Targeted Agents for In Vivo Molecular Imaging. Chow CY, King GF. Toxins (Basel) 16 307 (2024)
  3. Structural biology and molecular pharmacology of voltage-gated ion channels. Huang J, Pan X, Yan N. Nat Rev Mol Cell Biol (2024)
  4. Structural modeling of ion channels using AlphaFold2, RoseTTAFold2, and ESMFold. Nguyen PT, Harris BJ, Mateos DL, González AH, Murray AM, Yarov-Yarovoy V. Channels (Austin) 18 2325032 (2024)

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