title: Molecular mechanism of δ-dendrotoxin-potassium channel recognition explored by docking and molecular dynamic simulations.
abstract: δ-Dendrotoxin, isolated from mamba snake venom, has 57 residues cross-linked by three disulfide bridges. The protein shares a pharmacological activity with other animal toxins, the potent blockade of potassium channels, but is structurally unrelated to toxins of different species. We employed alanine-scanning mutagenesis to explore the molecular mechanism of δ-dendrotoxin binding to potassium channels, using protein-protein docking and molecular dynamic simulations. In our reasonable model of the δ-dendrotoxin-ShaKv1.1 complex, δ-dendrotoxin interacted mainly with the N-terminal region and the turn of two antiparallel β-sheets of the channel. This binding mode could well explain the functional roles of critical residues in δ-dendrotoxin and the ShaKv1.1 channel. Structural analysis indicated that the critical Lys6 residue of δ-dendrotoxin plugged its side chain into a channel selectivity filter. Another two critical δ-dendrotoxin residues, Lys3 and Arg10, were found to contact channel residues through strong polar and nonpolar interactions, especially salt-bridge interactions. As for the ShaKv1.1 channel, the channel turrets were found in the "half-open state," and two of four Glu423 in the turrets of the channel B and D chains could interact, respectively, with Lys3 and Lys26 of δ-dendrotoxin through electrostatic interactions. The essential Asp431 channel residue was found to associate electrostatically with Arg10 of δ-dendrotoxin, and a critical Tyr449 channel residue was just under the channel-interacting surface of δ-dendrotoxin. Together, these novel data may accelerate the structure-function research of toxins in the dendrotoxin family and be of significant value in revealing the diverse interactions between animal toxins and potassium channels.
authors.affiliation: Department of Chemistry, School of Natural Science, Wuhan University of Technology, Wuhan, Hubei 430070, P.R. China. lingjin@whut.edu.cn
authors.forename: Ling
authors.initials: L
authors.lastname: Jin
authors.forename: Yingliang
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000596:Amino Acids / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D004546:Elapid Venoms / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D026902:Potassium Channel Blockers / Q000378:metabolism; D015221:Potassium Channels / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D055550:Protein Stability; D020836:Protein Structure, Quaternary
chemical_list: D000596:Amino Acids; D004546:Elapid Venoms; D026902:Potassium Channel Blockers; D015221:Potassium Channels; C020273:dendrotoxin