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TitleStructural basis for voltage-sensor trapping of the cardiac sodium channel by a deathstalker scorpion toxin.
Journal, issue, pagesNat Commun, Vol. 12, Issue 1, Page 128, Year 2021
Publish dateJan 4, 2021
AuthorsDaohua Jiang / Lige Tonggu / Tamer M Gamal El-Din / Richard Banh / Régis Pomès / Ning Zheng / William A Catterall /
PubMed AbstractVoltage-gated sodium (Na) 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 ...Voltage-gated sodium (Na) 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 Na1.5 channels with IC = 11.4 nM. Here we reveal the structure of LqhIII bound to Na1.5 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 Na 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 Na channels.
External linksNat Commun / PubMed:33397917 / PubMed Central
MethodsEM (single particle)
Resolution3.3 Å
Structure data

22621

7k18

EMDB-22621, PDB-7k18:
Cardiac Sodium channel with toxin bound
Method: EM (single particle) / Resolution: 3.3 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-6OU:
[(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate / phospholipid*YM

Source
  • rattus norvegicus (Norway rat)
  • leiurus hebraeus (scorpion)
  • aequorea victoria (jellyfish)
  • Deathstalker scorpion (unknown)
KeywordsMEMBRANE PROTEIN / Ion channel / Toxin bound

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