Diverse binding poses of agonistic neurotoxins on human Na(v)1.6.

This study highlights the diverse binding mechanisms of peptide toxins on Na(v) channels, which could inform future therapeutic designs.

Summary and findings

This study examined the binding poses of three agonistic peptide toxins on the human Na(v)1.6-β1 channel complex using cryo-electron microscopy. It aimed to elucidate the mechanisms of action of these toxins to inform therapeutic development targeting Na(v) channels. Functional characterizations were also performed to support the findings.

Abstract

Voltage-gated sodium (Nav) channels are key targets of various venomous toxins. Deciphering the binding poses and mechanisms of action of representative toxins will help to dissect the functional mechanism of the channels and facilitate therapeutic development targeting Nav channels1,2. Here we present cryo-electron microscopy (cryo-EM) structures of distinct binding poses of three agonistic peptide toxins on the human Nav1.6-β1 channel complex. The globular β-scorpion toxin Cn2 nestles between the extracellular segment of voltage-sensing domain (VSD) in the second repeat of the Nav1.6 core α-unit (VSDII) and the pore extracellular loops in the third repeat of the Nav1.6 core α-unit (ECLIII), where it is stabilized by interactions with both protein regions and the branched N1372-glycan. Cone snail ι-conotoxin RXIA adopts 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 exists as a transmembrane helix that stands between VSDII and PDIII. Our findings, corroborated by functional characterizations, illustrate the diversity in peptide toxin binding poses and mechanisms of action, link stabilization of the up state of VSDI or VSDII to channel activation, and provide clues to the rational design of selective Nav channel modulators.

Limitations

Not reported in abstract.

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