Abstract
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.
Keywords:
block; neurotoxin; pore modulation; potassium channels; structural water.
Publication types
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Research Support, Non-U.S. Gov't
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Video-Audio Media
MeSH terms
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Animals
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Cell Membrane / drug effects*
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Cell Membrane / metabolism
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Crystallography, X-Ray
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Drosophila Proteins / antagonists & inhibitors*
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Drosophila Proteins / genetics
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Drosophila Proteins / isolation & purification
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Drosophila Proteins / metabolism
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Drug Design
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Female
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Hydrogen Bonding / drug effects
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Ion Channel Gating / drug effects*
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Kv1.2 Potassium Channel / antagonists & inhibitors*
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Kv1.2 Potassium Channel / genetics
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Kv1.2 Potassium Channel / isolation & purification
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Kv1.2 Potassium Channel / metabolism
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Lethal Dose 50
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Molecular Docking Simulation
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Molecular Dynamics Simulation
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Mollusk Venoms / chemistry
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Mollusk Venoms / toxicity*
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Mutation
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Oocytes
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Recombinant Proteins / genetics
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Recombinant Proteins / isolation & purification
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Recombinant Proteins / metabolism
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Shaker Superfamily of Potassium Channels / antagonists & inhibitors*
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Shaker Superfamily of Potassium Channels / genetics
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Shaker Superfamily of Potassium Channels / isolation & purification
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Shaker Superfamily of Potassium Channels / metabolism
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Water / chemistry
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Water / metabolism
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Xenopus laevis
Substances
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Drosophila Proteins
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Kv1.2 Potassium Channel
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Mollusk Venoms
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Recombinant Proteins
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Sh protein, Drosophila
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Shaker Superfamily of Potassium Channels
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conkunitzin-S1, Conus striatus
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Water