Toxin-induced conformational changes in a potassium channel revealed by solid-state NMR

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Abstract
The active site of potassium (K+) channels catalyses the transport of K+ ions across the plasma membrane1—similar to the catalytic function of the active site of an enzyme—and is inhibited by toxins from scorpion venom. On the basis of the conserved structures of K+ pore regions2 and scorpion toxins3,4, detailed structures for the K+ channel–scorpion toxin binding interface have been proposed. In these models and in previous solution-state nuclear magnetic resonance (NMR) studies using detergent-solubilized membrane proteins5,6, scorpion toxins were docked to the extracellular entrance of the K+ channel pore assuming rigid, preformed binding sites7,8,9,10,11,12,13. Using high-resolution solid-state NMR spectroscopy, here we show that high-affinity binding of the scorpion toxin kaliotoxin to a chimaeric K+ channel (KcsA-Kv1.3)14,15 is associated with significant structural rearrangements in both molecules. Our approach involves a combined analysis of chemical shifts and proton–proton distances and demonstrates that solid-state NMR is a sensitive method for analysing the structure of a membrane protein–inhibitor complex. We propose that structural flexibility of the K+ channel and the toxin represents an important determinant for the high specificity of toxin–K+ channel interactions.