Molecular interaction of δ-conotoxins with voltage-gated sodium channels

Various neurotoxic peptides modulate voltage-gated sodium (NaV) channels and thereby affect cellular excitability. δ-Conotoxins from predatory cone snails slow down inactivation of NaV channels, but their interaction site and mechanism of channel modulation are unknown. Here, we show that δ-conotoxin SVIE from Conus striatus interacts with a conserved hydrophobic triad (YFV) in the domain-4 voltage sensor of NaV channels. This site overlaps with that of the scorpion α-toxin Lqh-2, but not with the α-like toxin Lqh-3 site. δ-SVIE functionally competes with Lqh-2, but exhibits strong cooperativity with Lqh-3, presumably by synergistically trapping the voltage sensor in its “on” position.