Journal Article

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

Szanto, Tibor, Gordon, Dalia, Gurevitz, Michael, Karbat, Izhar, Frolow, Felix, Panyi, Gyorgy, Altman-Gueta, Hagit, Dym, Orly, Reuveny, Eitan, Fine, Shachar, Hamer-Rogotner, Shelly

2019

Overview

Voltage-dependent potassium channels (Kvs) gate in response to changes in electrical membrane potential by coupling a voltage-sensing module with a K⁺-selective pore. Animal toxins targeting Kvs 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 Kv1.2 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.

• Publisher: National Academy of Sciences
• Subject: Animals / Biological Sciences / Cell Membrane - drug effects / Cell Membrane - metabolism / Channel gating / Channels / Collapse / Crystallography, X-Ray / Deactivation / Drosophila Proteins - antagonists & inhibitors / Drosophila Proteins - genetics / Drosophila Proteins - isolation & purification / Drosophila Proteins - metabolism / Drug Design / Drug development / Electric potential / Female / Holes / Hydrogen bonding / Hydrogen Bonding - drug effects / Hydrogen bonds / Inactivation / Ion Channel Gating - drug effects / Kv1.2 Potassium Channel - antagonists & inhibitors / Kv1.2 Potassium Channel - genetics / Kv1.2 Potassium Channel - isolation & purification / Kv1.2 Potassium Channel - metabolism / Lethal Dose 50 / Membrane potential / Molecular Docking Simulation / Molecular Dynamics Simulation / Mollusk Venoms - chemistry / Mollusk Venoms - toxicity / Mutation / Oocytes / Physiology / PNAS Plus / Potassium / Potassium channels (voltage-gated) / Recombinant Proteins - genetics / Recombinant Proteins - isolation & purification / Recombinant Proteins - metabolism / Shaker Superfamily of Potassium Channels - antagonists & inhibitors / Shaker Superfamily of Potassium Channels - genetics / Shaker Superfamily of Potassium Channels - isolation & purification / Shaker Superfamily of Potassium Channels - metabolism / Toxins / Venom / Voltage / Water - chemistry / Water - metabolism / Water flow / Xenopus laevis