BPS2026 – Structural and functional characterization of promiscuous scorpion toxins OSK1 and HeLaTx1 on muscle-type nAChR

Muscle-type nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels essential for neuromuscular transmission. Venom peptides are powerful probes of such receptor function, often revealing fundamental principles of channel regulation. Here, we investigated the scorpion toxins OSK1 ( Orthochirus scrobiculosus ) and HeLaTx1 ( Heterometrus laoticus ), which are particularly interesting because they not only inhibit ligand-gated receptors such as nAChR but also block voltage-gated potassium channels. To explore how a single toxin engages these structurally distinct channel families, we combined computational modeling, cryogenic electron microscopy (cryo-EM), and electrophysiology. Complementary cryo-EM reconstructions of toxin-receptor complexes identified the binding sites of the toxins, while electrophysiological recordings demonstrated the functional consequences of toxin engagement. Parallel modeling of OSK1 bound to Kv channels revealed overlapping structural motifs that may underlie its ability to modulate divergent ion channel classes. These findings demonstrate how scorpion toxins exploit conserved structural features to cross-target ligand-gated and voltage-gated channels. By uncovering shared strategies of ion channel inhibition by natural peptides, this work broadens our understanding of excitability regulation and illustrates how venoms can inspire new approaches to probing ion channel function.