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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: 42 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)

  1. Structural Advances in Voltage-Gated Sodium Channels. Jiang D, Zhang J, Xia Z. Front Pharmacol 13 908867 (2022)
  2. P-Loop Channels: Experimental Structures, and Physics-Based and Neural Networks-Based Models. Tikhonov DB, Zhorov BS. Membranes (Basel) 12 229 (2022)
  3. A structural atlas of druggable sites on Nav channels. Li Z, Wu Q, Yan N. Channels (Austin) 18 2287832 (2024)

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  1. Polycystin Channel Complexes. Esarte Palomero O, Larmore M, DeCaen PG. Annu Rev Physiol 85 425-448 (2023)
  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. Voltage gated sodium and calcium channels: Discovery, structure, function, and Pharmacology. Catterall WA. Channels (Austin) 17 2281714 (2023)
  4. Electron microscopy of cardiac 3D nanodynamics: form, function, future. Kohl P, Greiner J, Rog-Zielinska EA. Nat Rev Cardiol 19 607-619 (2022)
  5. Conotoxins Targeting Voltage-Gated Sodium Ion Channels. Pei S, Wang N, Mei Z, Zhangsun D, Craik DJ, McIntosh JM, Zhu X, Luo S. Pharmacol Rev 76 828-845 (2024)
  6. Structural biology and molecular pharmacology of voltage-gated ion channels. Huang J, Pan X, Yan N. Nat Rev Mol Cell Biol 25 904-925 (2024)

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