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.
Highlights
Voltage-gated sodium (NaV) channels initiate action potentials in excitable cells, and their function is altered by potent gating-modifier toxins
This effect of LqhIII and other α-scorpion toxins is achieved by trapping the voltage sensor (VS) in domain IV (DIV) of sodium channels in a conformation that allows sodium channel activation but prevents coupling to fast inactivation[4,9,10]
Biochemical and biophysical studies support only a single neurotoxin receptor site 3 per sodium channel located in the VS in DIV, at which αscorpion toxins, sea anemone toxins, and related gating-modifier toxins bind[9,10]
Summary
Voltage-gated sodium (NaV) channels initiate action potentials in excitable cells, and their function is altered by potent gating-modifier toxins. 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. 3, dramatically inhibit fast inactivation of NaV channels, and cause prolonged and/or repetitive action potentials[3,4,5] Scorpions utilize these toxins in their venoms to immobilize prey by inducing paralysis and causing cardiac arrhythmia[4,6,7,8].
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