National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)
HL112808
United States
Howard Hughes Medical Institute (HHMI)
United States
Citation
Journal: Nat Commun / Year: 2021 Title: Structural basis for voltage-sensor trapping of the cardiac sodium channel by a deathstalker scorpion toxin. Authors: Daohua Jiang / Lige Tonggu / Tamer M Gamal El-Din / Richard Banh / Régis Pomès / Ning Zheng / William A Catterall / Abstract: 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 ...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.
Sodiumchannelproteintype5subunitalpha, EnhancedGreenfluorescentprotein / Sodium channel protein cardiac muscle subunit alpha / Sodium channel protein type V subunit alpha / ...Sodium channel protein cardiac muscle subunit alpha / Sodium channel protein type V subunit alpha / Voltage-gated sodium channel subunit alpha Nav1.5
Mass: 209037.781 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Details: Loops truncated sodium channel with EGFP and FLAG tag fused at the C-terminus Source: (gene. exp.) Rattus norvegicus (Norway rat), (gene. exp.) Aequorea victoria (jellyfish) Gene: Scn5a, GFP / Cell line (production host): HEK293S / Production host: Homo sapiens (human) / References: UniProt: P15389, UniProt: P42212
#2: Protein
Alpha-liketoxinLqh3 / Lqh III / LqhIII
Mass: 7065.984 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Leiurus hebraeus (scorpion) / References: UniProt: P56678
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