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

TY - JOUR

T1 - Toxin-induced conformational changes in a potassium channel revealed by solid-state NMR

AU - Lange, Adam

AU - Giller, Karin

AU - Hornig, Sönke

AU - Martin-Eauclaire, Marie-France

AU - Pongs, Olaf

AU - Becker, Stefan

AU - Baldus, Marc

PY - 2006/4/13

Y1 - 2006/4/13

N2 - The active site of potassium (K+) channels catalyses the transport of K+ ions across the plasma membrane--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 regions and scorpion toxins, 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, scorpion toxins were docked to the extracellular entrance of the K+ channel pore assuming rigid, preformed binding sites. 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) 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.

AB - The active site of potassium (K+) channels catalyses the transport of K+ ions across the plasma membrane--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 regions and scorpion toxins, 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, scorpion toxins were docked to the extracellular entrance of the K+ channel pore assuming rigid, preformed binding sites. 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) 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.

KW - Amino Acid Sequence

KW - Animals

KW - Bacterial Proteins

KW - Kv1.3 Potassium Channel

KW - Models, Molecular

KW - Molecular Sequence Data

KW - Mutation

KW - Nuclear Magnetic Resonance, Biomolecular

KW - Oocytes

KW - Potassium Channel Blockers

KW - Potassium Channels

KW - Protein Conformation

KW - Recombinant Fusion Proteins

KW - Scorpion Venoms

KW - Scorpions

KW - Xenopus

U2 - 10.1038/nature04649

DO - 10.1038/nature04649

M3 - SCORING: Journal article

C2 - 16612389

VL - 440

SP - 959

EP - 962

JO - NATURE

JF - NATURE

SN - 0028-0836

IS - 7086

ER -