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Structural basis for voltage-sensor trapping of the cardiac sodium channel by a deathstalker scorpion toxin.

<div class='caption-title'>Block of fast inactivation of rNaV1.5C by LqhIII.</div>
<div class='caption-title'>Cryo-EM structure of the rNaV1.5C/LqhIII complex.</div>
<div class='caption-title'>Overall structure of rNaV1.5C/LqhIII complex and LqhIII binding site.</div>
Jiang D, Tonggu L, Gamal El-Din TM, Banh R, Pomès R, Zheng N, Catterall WA
OpenAccess logo Nat Commun 12 128 (2021)
Cited: 36 times
EuropePMC logo PMID: 33397917

Abstract

Voltage-gated sodium (NaV) channels initiate action potentials in excitable cells, and their function is altered by potent gating-modifier toxins. The α-toxin LqhIII from the deathstalker scorpion inhibits fast inactivation of cardiac NaV1.5 channels with IC50 = 11.4 nM. Here we reveal the structure of LqhIII bound to NaV1.5 at 3.3 Å resolution by cryo-EM. LqhIII anchors on top of voltage-sensing domain IV, wedged between the S1-S2 and S3-S4 linkers, which traps the gating charges of the S4 segment in a unique intermediate-activated state stabilized by four ion-pairs. This conformational change is propagated inward to weaken binding of the fast inactivation gate and favor opening the activation gate. However, these changes do not permit Na+ permeation, revealing why LqhIII slows inactivation of NaV channels but does not open them. Our results provide important insights into the structural basis for gating-modifier toxin binding, voltage-sensor trapping, and fast inactivation of NaV channels.

Reviews - 7k18 mentioned but not cited (3)

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Articles - 7k18 mentioned but not cited (6)

  1. Open-state structure and pore gating mechanism of the cardiac sodium channel. Jiang D, Banh R, Gamal El-Din TM, Tonggu L, Lenaeus MJ, Pomès R, Zheng N, Catterall WA. Cell 184 5151-5162.e11 (2021)
  2. Structure of human Cav2.2 channel blocked by the painkiller ziconotide. Gao S, Yao X, Yan N. Nature 596 143-147 (2021)
  3. Possible Interactions of Extracellular Loop IVP2-S6 With Voltage-Sensing Domain III in Cardiac Sodium Channel. Zaytseva AK, Boitsov AS, Kostareva AA, Zhorov BS. Front Pharmacol 12 742508 (2021)
  4. An open state of a voltage-gated sodium channel involving a π-helix and conserved pore-facing asparagine. Choudhury K, Kasimova MA, McComas S, Howard RJ, Delemotte L. Biophys J 121 11-22 (2022)
  5. Computational Analysis of the Crystal and Cryo-EM Structures of P-Loop Channels with Drugs. Tikhonov DB, Zhorov BS. Int J Mol Sci 22 8143 (2021)
  6. Molecular Modeling of Cardiac Sodium Channel with Mexiletine. Zhorov BS. Membranes (Basel) 12 1252 (2022)


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  2. Druggability of Voltage-Gated Sodium Channels-Exploring Old and New Drug Receptor Sites. Wisedchaisri G, Gamal El-Din TM. Front Pharmacol 13 858348 (2022)
  3. Electron microscopy of cardiac 3D nanodynamics: form, function, future. Kohl P, Greiner J, Rog-Zielinska EA. Nat Rev Cardiol (2022)
  4. Polycystin Channel Complexes. Esarte Palomero O, Larmore M, DeCaen PG. Annu Rev Physiol 85 425-448 (2023)

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  2. Unwinding and spiral sliding of S4 and domain rotation of VSD during the electromechanical coupling in Nav1.7. Huang G, Wu Q, Li Z, Jin X, Huang X, Wu T, Pan X, Yan N. Proc Natl Acad Sci U S A 119 e2209164119 (2022)
  3. Voltage-gating and cytosolic Ca2+ activation mechanisms of Arabidopsis two-pore channel AtTPC1. Ye F, Xu L, Li X, Zeng W, Gan N, Zhao C, Yang W, Jiang Y, Guo J. Proc Natl Acad Sci U S A 118 e2113946118 (2021)
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  5. Characterizing fenestration size in sodium channel subtypes and their accessibility to inhibitors. Tao E, Corry B. Biophys J 121 193-206 (2022)
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  10. Differential regulation of cardiac sodium channels by intracellular fibroblast growth factors. Angsutararux P, Dutta AK, Marras M, Abella C, Mellor RL, Shi J, Nerbonne JM, Silva JR. J Gen Physiol 155 e202213300 (2023)
  11. Editorial Editorial: Structure Related Druggability of Voltage-Gated Sodium and Calcium Ion-Channels to Treat Diseases. Gamal El-Din TM, Zimmer T, Chahine M. Front Pharmacol 13 947511 (2022)
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  14. Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain. Manville RW, Alfredo Freites J, Sidlow R, Tobias DJ, Abbott GW. Nat Commun 14 3281 (2023)
  15. Naview: A d3.js Based JavaScript Library for Drawing and Annotating Voltage-Gated Sodium Channels Membrane Diagrams. Afonso MQL, da Fonseca Júnior NJ, Miranda TG, Bleicher L. Front Bioinform 2 774417 (2022)
  16. Pyrethroids in an AlphaFold2 Model of the Insect Sodium Channel. Zhorov BS, Dong K. Insects 13 745 (2022)
  17. Structural and Functional Characterization of a Novel Scorpion Toxin that Inhibits NaV1.8 via Interactions With the DI Voltage Sensor and DII Pore Module. George K, Lopez-Mateos D, Abd El-Aziz TM, Xiao Y, Kline J, Bao H, Raza S, Stockand JD, Cummins TR, Fornelli L, Rowe MP, Yarov-Yarovoy V, Rowe AH. Front Pharmacol 13 846992 (2022)
  18. 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)
  19. Structural basis for modulation of human NaV1.3 by clinical drug and selective antagonist. 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. Nat Commun 13 1286 (2022)
  20. Structural basis for severe pain caused by mutations in the S4-S5 linkers of voltage-gated sodium channel NaV1.7. Wisedchaisri G, Gamal El-Din TM, Zheng N, Catterall WA. Proc Natl Acad Sci U S A 120 e2219624120 (2023)
  21. 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)
  22. Targeting the tamoxifen receptor within sodium channels to block osteoarthritic pain. McCollum MM, Larmore M, Ishihara S, Ng LCT, Kimura LF, Guadarrama E, Ta MC, Vien TN, Frost GB, Scheidt KA, Miller RE, DeCaen PG. Cell Rep 40 111248 (2022)
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