Scorpion and cone snail neurotoxins reveal diverse binding poses on human Nav1.6, linking structural stabilization to channel activation.

Voltage-gated sodium (Nav) channels are critical for neuronal excitability, making them prime targets for therapeutic intervention. Dysregulation of specific subtypes, particularly Nav1.6, is a core mechanism underlying conditions like epileptogenesis and associated neuropsychiatric comorbidities. Current treatments often lack specificity, leading to off-target effects. Venom-derived peptides, such as those from scorpions and cone snails, offer a promising avenue due to their high specificity for ion channels, potentially leading to novel analgesics or anticonvulsants that bypass opioid pathways.

Researchers utilized cryo-electron microscopy (cryo-EM) to determine the distinct binding poses of three agonistic peptide toxins on the human Nav1.6-β1 channel complex. The study investigated the globular β-scorpion toxin Cn2, the cone snail ι-conotoxin RXIA, and the bullet ant-derived toxin δ-paraponeritoxin-Pc1a. These structural analyses were corroborated by functional characterizations to understand how these diverse binding modes translate into channel activation and modulation.

The study revealed three distinct binding poses for the agonistic peptide toxins on the human Nav1.6-β1 channel complex. The globular β-scorpion toxin Cn2 was found to nestle between the extracellular segment of the voltage-sensing domain in the second repeat (VSDII) and the pore extracellular loops in the third repeat (ECLIII) of the Nav1.6 core α-unit. This binding was stabilized by interactions with both protein regions and the branched N1372-glycan. In contrast, cone snail ι-conotoxin RXIA adopted an elongated conformation, spanning VSDI and VSDIV to wrap around the shoulder of the pore domain (PD). The bullet ant-derived toxin δ-paraponeritoxin-Pc1a existed as a transmembrane helix, positioned between VSDII and PDIII.