title: The molecular mechanism of toxin-induced conformational changes in a potassium channel: relation to C-type inactivation.
abstract: Recently, a solid-state NMR study revealed that scorpion toxin binding leads to conformational changes in the selectivity filter of potassium channels. The exact nature of the conformational changes, however, remained elusive. We carried out all-atom molecular dynamics simulations that enabled us to cover the complete pathway of toxin approach and binding, and we validated our simulation results by using solid-state NMR data and electrophysiological measurements. Our structural model revealed a mechanism of cooperative toxin-induced conformational changes that accounts both for the signal changes observed in solid-state NMR and for the tight interaction between KcsA-Kv1.3 and Kaliotoxin. We show that this mechanism is structurally and functionally closely related to recovery from C-type inactivation. Furthermore, our simulations indicate heterogeneity in the binding modes of Kaliotoxin, which might serve to enhance its affinity for KcsA-Kv1.3 further by entropic stabilization.
authors.affiliation: Computational Biomolecular Dynamics Group, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Zachariae
authors.forename: Robert
authors.initials: R
authors.lastname: Schneider
authors.forename: Phanindra
authors.initials: P
authors.lastname: Velisetty
authors.forename: Adam
authors.initials: A
authors.lastname: Lange
authors.forename: Daniel
authors.initials: D
authors.lastname: Seeliger
authors.forename: Sören J
authors.initials: SJ
authors.lastname: Wacker
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Karimi-Nejad
authors.forename: Gert
authors.initials: G
authors.lastname: Vriend
authors.forename: Stefan
authors.initials: S
authors.lastname: Becker
authors.forename: Olaf
authors.initials: O
authors.lastname: Pongs
authors.forename: Marc
authors.initials: M
authors.lastname: Baldus
authors.forename: Bert L
authors.initials: BL
authors.lastname: de Groot
mesh_terms: D000818:Animals; D003198:Computer Simulation; D004594:Electrophysiology; D005260:Female; D051664:Kv1.3 Potassium Channel / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008845:Microinjections; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated; D017433:Protein Structure, Secondary; D018075:RNA, Complementary / Q000008:administration & dosage; D012604:Scorpion Venoms / Q000737:chemistry / Q000378:metabolism*; D012605:Scorpions; D055672:Static Electricity; D014981:Xenopus
chemical_list: D051664:Kv1.3 Potassium Channel; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D018075:RNA, Complementary; D012604:Scorpion Venoms; C072276:kaliotoxin