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

• DOI: 10.1073/pnas.1908903116
• Publication Date: 2019-08-23T21:45:26Z
• Authors: Izhar Karbat; Hagit Altman-Gueta; Shachar Fine; Tibor Szanto; Shelly Hamer-Rogo...; Orly Dym; Felix Frolow; Dalia Gordon; Gyorgy Panyi; Michael Gurevitz; Eitan Reuveny
• Keywords: 0301 basic medicine; Cell Membrane; Mollusk Venoms; Water; Hydrogen Bonding; Molecular Dynamics Simulation; Crystallography, X-Ray; Recombinant Proteins; Lethal Dose 50; Molecular Docking Simulation; Xenopus laevis; 03 medical and health sciences; Drug Design; Mutation; Kv1.2 Potassium Channel; Oocytes; Shaker Superfamily of Potassium Channels; Animals; Drosophila Proteins; Female; Ion Channel Gating

Voltage-dependent potassium channels (K v s) gate in response to changes in electrical membrane potential by coupling a voltage-sensing module with a K + -selective pore. Animal toxins targeting K v s 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 v 1.2 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.