National Academy of Sciences, Proceedings of the National Academy of Sciences, 50(112), 2015
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Significance Peptide neurotoxins that inhibit specific ion channels are valuable for research and clinical care but unknown for most targets. Here we consider KcsA, an orphan potassium channel with no known toxin. We build a phage-display library expressing natural toxins related to the sea anemone toxin ShK and 1.5 million novel combinatorial variants. Peptides that bind tightly to KcsA are isolated and two are described: Hui1 is novel and specific for KcsA, and HmK is natural and promiscuous. The 3D structure and action of Hui1 validate our strategy and reveal an unexpected basis for channel inhibition wherein an arginine side chain, too large to enter the conduction pathway, interacts with potassium ions traversing the pore from the other side of the membrane.