Pore-modulating toxins exploit inherent slow inactivation to block K⁺ channels

Voltage-dependent potassium channels (K_vs) gate in response to changes in electrical membrane potential by coupling a voltage-sensing module with a K⁺-selective pore. Animal toxins targeting K_vs are classified as pore blockers, which physically plug the ion conduction pathway, or as gating modifiers, which disrupt voltage sensor movements. A third group of toxins blocks K⁺ conduction by an unknown mechanism via binding to the channel turrets. Here, we show that Conkunitzin-S1 (Cs1), a peptide toxin isolated from cone snail venom, binds at the turrets of K_v1.2 and targets a network of hydrogen bonds that govern water access to the peripheral cavities that surround the central pore. The resulting ectopic water flow triggers an asymmetric collapse of the pore by a process resembling that of inherent slow inactivation. Pore modulation by animal toxins exposes the peripheral cavity of K⁺ channels as a novel pharmacological target and provides a rational framework for drug design.