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

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 toxins^3,4, 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 proteins^5,6, scorpion toxins were docked to the extracellular entrance of the K⁺ channel pore assuming rigid, preformed binding sites^{7,8,9,10,11,12,13}. 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.