Molecular mechanism of δ-dendrotoxin–potassium channel recognition explored by docking and molecular dynamic simulations
✍ Scribed by Ling Jin; Yingliang Wu
- Publisher
- John Wiley and Sons
- Year
- 2010
- Tongue
- English
- Weight
- 786 KB
- Volume
- 24
- Category
- Article
- ISSN
- 0952-3499
- DOI
- 10.1002/jmr.1031
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✦ Synopsis
d-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 d-dendrotoxin binding to potassium channels, using protein-protein docking and molecular dynamic simulations. In our reasonable model of the d-dendrotoxin-ShaKv1.1 complex, d-dendrotoxin interacted mainly with the N-terminal region and the turn of two antiparallel b-sheets of the channel. This binding mode could well explain the functional roles of critical residues in d-dendrotoxin and the ShaKv1.1 channel. Structural analysis indicated that the critical Lys6 residue of d-dendrotoxin plugged its side chain into a channel selectivity filter. Another two critical d-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 d-dendrotoxin through electrostatic interactions. The essential Asp431 channel residue was found to associate electrostatically with Arg10 of d-dendrotoxin, and a critical Tyr449 channel residue was just under the channel-interacting surface of d-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.