title: 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 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.
authors.affiliation: Max Planck Institute for Biophysical Chemistry, Department of NMR-Based Structural Biology, 37077 Göttingen, Germany.
authors.forename: Adam
authors.initials: A
authors.lastname: Lange
authors.forename: Karin
authors.initials: K
authors.lastname: Giller
authors.forename: Sönke
authors.initials: S
authors.lastname: Hornig
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Martin-Eauclaire
authors.forename: Olaf
authors.initials: O
authors.lastname: Pongs
authors.forename: Stefan
authors.initials: S
authors.lastname: Becker
authors.forename: Marc
authors.initials: M
authors.lastname: Baldus
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D051664:Kv1.3 Potassium Channel / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular; D009865:Oocytes / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015221:Potassium Channels / Q000737:chemistry* / Q000187:drug effects* / Q000378:metabolism; D011487:Protein Conformation / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D012604:Scorpion Venoms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D012605:Scorpions; D014981:Xenopus
chemical_list: D001426:Bacterial Proteins; D051664:Kv1.3 Potassium Channel; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011993:Recombinant Fusion Proteins; D012604:Scorpion Venoms; C072276:kaliotoxin; C107790:prokaryotic potassium channel