1. Pore-modulating toxins exploit inherent slow inactivation to block K + channels.
- Author
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Karbat I, Altman-Gueta H, Fine S, Szanto T, Hamer-Rogotner S, Dym O, Frolow F, Gordon D, Panyi G, Gurevitz M, and Reuveny E
- Subjects
- Animals, Cell Membrane metabolism, Crystallography, X-Ray, Drosophila Proteins genetics, Drosophila Proteins isolation & purification, Drosophila Proteins metabolism, Drug Design, Female, Hydrogen Bonding drug effects, Kv1.2 Potassium Channel genetics, Kv1.2 Potassium Channel isolation & purification, Kv1.2 Potassium Channel metabolism, Lethal Dose 50, Molecular Docking Simulation, Molecular Dynamics Simulation, Mollusk Venoms chemistry, Mutation, Oocytes, Recombinant Proteins genetics, Recombinant Proteins isolation & purification, Recombinant Proteins metabolism, Shaker Superfamily of Potassium Channels genetics, Shaker Superfamily of Potassium Channels isolation & purification, Shaker Superfamily of Potassium Channels metabolism, Water chemistry, Water metabolism, Xenopus laevis, Cell Membrane drug effects, Drosophila Proteins antagonists & inhibitors, Ion Channel Gating drug effects, Kv1.2 Potassium Channel antagonists & inhibitors, Mollusk Venoms toxicity, Shaker Superfamily of Potassium Channels antagonists & inhibitors
- Abstract
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 Kv 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 Kv 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., Competing Interests: The authors declare no conflict of interest.- Published
- 2019
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