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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)

  1. Dual receptor-sites reveal the structural basis for hyperactivation of sodium channels by poison-dart toxin batrachotoxin. Tonggu L, Wisedchaisri G, Gamal El-Din TM, Lenaeus MJ, Logan MM, Toma T, Du Bois J, Zheng N, Catterall WA. Nat Commun 15 2306 (2024)
  2. In Silico drug repurposing pipeline using deep learning and structure based approaches in epilepsy. Lv X, Wang J, Yuan Y, Pan L, Liu Q, Guo J. Sci Rep 14 16562 (2024)


Reviews citing this publication (4)

  1. Pathology of pain and its implications for therapeutic interventions. Cao B, Xu Q, Shi Y, Zhao R, Li H, Zheng J, Liu F, Wan Y, Wei B. Signal Transduct Target Ther 9 155 (2024)
  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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  1. Cryo-EM structure of human voltage-gated sodium channel Nav1.6. Fan X, Huang J, Jin X, Yan N. Proc Natl Acad Sci U S A 120 e2220578120 (2023)
  2. Structural mapping of Nav1.7 antagonists. Wu Q, Huang J, Fan X, Wang K, Jin X, Huang G, Li J, Pan X, Yan N. Nat Commun 14 3224 (2023)
  3. Cannabidiol inhibits Nav channels through two distinct binding sites. Huang J, Fan X, Jin X, Jo S, Zhang HB, Fujita A, Bean BP, Yan N. Nat Commun 14 3613 (2023)
  4. Structural basis for NaV1.7 inhibition by pore blockers. Zhang J, Shi Y, Huang Z, Li Y, Yang B, Gong J, Jiang D. Nat Struct Mol Biol 29 1208-1216 (2022)
  5. Structure of human NaV1.6 channel reveals Na+ selectivity and pore blockade by 4,9-anhydro-tetrodotoxin. Li Y, Yuan T, Huang B, Zhou F, Peng C, Li X, Qiu Y, Yang B, Zhao Y, Huang Z, Jiang D. Nat Commun 14 1030 (2023)
  6. Structural modeling of the hERG potassium channel and associated drug interactions. Maly J, Emigh AM, DeMarco KR, Furutani K, Sack JT, Clancy CE, Vorobyov I, Yarov-Yarovoy V. Front Pharmacol 13 966463 (2022)
  7. Cryo-EM reveals an unprecedented binding site for NaV1.7 inhibitors enabling rational design of potent hybrid inhibitors. Kschonsak M, Jao CC, Arthur CP, Rohou AL, Bergeron P, Ortwine DF, McKerrall SJ, Hackos DH, Deng L, Chen J, Li T, Dragovich PS, Volgraf M, Wright MR, Payandeh J, Ciferri C, Tellis JC. Elife 12 e84151 (2023)
  8. Design, synthesis, and mechanism of action of novel μ-conotoxin KIIIA analogues for inhibition of the voltage-gated sodium channel Nav1.7. Zhao Z, Pan T, Chen S, Harvey PJ, Zhang J, Li X, Yang M, Huang L, Wang S, Craik DJ, Jiang T, Yu R. J Biol Chem 299 103068 (2023)
  9. Inhibition of Voltage-Gated Na+ Currents Exerted by KB-R7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea), an Inhibitor of Na+-Ca2+ Exchanging Process. Wu SN, Yu MC. Int J Mol Sci 24 1805 (2023)
  10. Modulation of Pore Opening of Eukaryotic Sodium Channels by π-Helices in S6. Choudhury K, Delemotte L. J Phys Chem Lett 14 5876-5881 (2023)
  11. Cell-cycle arrest at the G1/S boundary enhances transient voltage-gated ion channel expression in human and insect cells. Eltokhi A, Catterall WA, Gamal El-Din TM. Cell Rep Methods 3 100559 (2023)
  12. Argentatin C Analogues with Potential Antinociceptive Activity and Other Triterpenoid Constituents from the Aerial Parts of Parthenium incanum. Xu YM, Wijeratne EMK, Calderon-Rivera A, Loya-López S, Perez-Miller S, Khanna R, Gunatilaka AAL. ACS Omega 8 20085-20095 (2023)
  13. Beta-subunit-eliminated eHAP expression (BeHAPe) cells reveal subunit regulation of the cardiac voltage-gated sodium channel. Minard AY, Clark CJ, Ahern CA, Piper RC. J Biol Chem 299 105132 (2023)
  14. Bulleyaconitine A reduces fracture-induced pain and promotes fracture healing in mice. Peng J, Xiao S, Xie J, Fu W. Front Pharmacol 14 1046514 (2023)
  15. Dissection of the structure-function relationship of Nav channels. Li Z, Wu Q, Huang G, Jin X, Li J, Pan X, Yan N. Proc Natl Acad Sci U S A 121 e2322899121 (2024)
  16. Molecular Pharmacology of Selective NaV1.6 and Dual NaV1.6/NaV1.2 Channel Inhibitors that Suppress Excitatory Neuronal Activity Ex Vivo. Goodchild SJ, Shuart NG, Williams AD, Ye W, Parrish RR, Soriano M, Thouta S, Mezeyova J, Waldbrook M, Dean R, Focken T, Ghovanloo MR, Ruben PC, Scott F, Cohen CJ, Empfield J, Johnson JP. ACS Chem Neurosci 15 1169-1184 (2024)
  17. Molecular determinants of μ-conotoxin KIIIA interaction with the human voltage-gated sodium channel NaV1.7. Kimball IH, Nguyen PT, Olivera BM, Sack JT, Yarov-Yarovoy V. Front Pharmacol 14 1156855 (2023)
  18. The binding and mechanism of a positive allosteric modulator of Kv3 channels. Liang Q, Chi G, Cirqueira L, Zhi L, Marasco A, Pilati N, Gunthorpe MJ, Alvaro G, Large CH, Sauer DB, Treptow W, Covarrubias M. Nat Commun 15 2533 (2024)
  19. VGSC-DB: an online database of voltage-gated sodium channels. Wang G, Yu J, Du H, Shen C, Zhang X, Liu Y, Zhang Y, Cao D, Pan P, Hou T. J Cheminform 14 75 (2022)
  20. Phylogeny, envenomation syndrome, and membrane permeabilising venom produced by Australia's electric caterpillar Comana monomorpha. Goudarzi MH, Robinson SD, Cardoso FC, Mitchell ML, Cook LG, King GF, Walker AA. Sci Rep 14 14172 (2024)
  21. Unplugging lateral fenestrations of NALCN reveals a hidden drug binding site within the pore region. Schott K, Usher SG, Serra O, Carnevale V, Pless SA, Chua HC. Proc Natl Acad Sci U S A 121 e2401591121 (2024)


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