title: Structural basis for the inhibition of voltage-dependent K+ channel by gating modifier toxin.
abstract: Voltage-dependent K(+) (Kv) channels play crucial roles in nerve and muscle action potentials. Voltage-sensing domains (VSDs) of Kv channels sense changes in the transmembrane potential, regulating the K(+)-permeability across the membrane. Gating modifier toxins, which have been used for the functional analyses of Kv channels, inhibit Kv channels by binding to VSD. However, the structural basis for the inhibition remains elusive. Here, fluorescence and NMR analyses of the interaction between VSD derived from KvAP channel and its gating modifier toxin, VSTx1, indicate that VSTx1 recognizes VSD under depolarized condition. We identified the VSD-binding residues of VSTx1 and their proximal residues of VSD by the cross-saturation (CS) and amino acid selective CS experiments, which enabled to build a docking model of the complex. These results provide structural basis for the specific binding and inhibition of Kv channels by gating modifier toxins.
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Ozawa
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nozaki
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Harada
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Ichio
authors.initials: I
authors.lastname: Shimada
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.|Keio University Faculty of Pharmacy, Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Osawa
mesh_terms: D001665:Binding Sites; D015640:Ion Channel Gating / Q000187:drug effects; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D026902:Potassium Channel Blockers / Q000737:chemistry* / Q000494:pharmacology*; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D013329:Structure-Activity Relationship; D014118:Toxins, Biological / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D014118:Toxins, Biological