25IJ

Cryo-EM structure of human Nav1.6 in complex with delta-paraponeritoxin-Pc1a

Summary for 25IJ

• Entry DOI: 10.2210/pdb25ij/pdb
• EMDB information: 80135
• Descriptor: Sodium channel protein type 8 subunit alpha, Delta-paraponeritoxin-Pc1a, Sodium channel regulatory subunit beta-1, ... (9 entities in total)
• Functional Keywords: nav1.6, voltage gated sodium channel, toxin, pc1a, delta-paraponeritoxin-pc1a, transport protein, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 255232.23

Authors

Yang, L.,Fan, X.,Huang, J.,Yan, N. (deposition date: 2026-04-06, release date: 2026-05-20, Last modification date: 2026-06-24)

Primary citation

Fan, X.,Huang, J.,Yang, L.,Chen, J.,Wang, H.,Huang, X.,Geng, J.,Wu, Q.,Xie, Y.,Lu, F.,Guo, Q.,Shen, Z.,Jin, X.,Yan, N.
Diverse binding poses of agonistic neurotoxins on human Na v 1.6.
Nature, 2026

PubMed Abstract: Voltage-gated sodium (Na) 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 Na channels. Here we present cryo-electron microscopy (cryo-EM) structures of distinct binding poses of three agonistic peptide toxins on the human Na1.6-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 Na1.6 core α-unit (VSD) and the pore extracellular loops in the third repeat of the Na1.6 core α-unit (ECL), 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 VSD and VSD 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 VSD and PD. 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 VSD or VSD to channel activation, and provide clues to the rational design of selective Na channel modulators.

PubMed: 42271061
DOI: 10.1038/s41586-026-10661-x

Experimental method

ELECTRON MICROSCOPY (3.1 Å)