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Mar. Drugs 2019, 17(3), 180; https://doi.org/10.3390/md17030180

In Silico Analysis of the Subtype Selective Blockage of KCNA Ion Channels through the µ-Conotoxins PIIIA, SIIIA, and GIIIA

1
Technische Universität Darmstadt, Eduard-Zintl-Institute for Inorganic and Physical Chemistry, Alarich-Weiss Str. 8, 64287 Darmstadt, Germany
2
University of Gothenburg, Department of Chemistry and Molecular Biology, Wallenberg Centre for Molecular and Translational Medicine, Kemigården 4, 41296 Göteborg, Sweden
*
Author to whom correspondence should be addressed.
Received: 21 February 2019 / Revised: 12 March 2019 / Accepted: 15 March 2019 / Published: 19 March 2019
(This article belongs to the Special Issue Bioinformatics of Marine Natural Products)
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Abstract

Understanding subtype specific ion channel pore blockage by natural peptide-based toxins is crucial for developing such compounds into promising drug candidates. Herein, docking and molecular dynamics simulations were employed in order to understand the dynamics and binding states of the µ-conotoxins, PIIIA, SIIIA, and GIIIA, at the voltage-gated potassium channels of the KV1 family, and they were correlated with their experimental activities recently reported by Leipold et al. Their different activities can only adequately be understood when dynamic information about the toxin-channel systems is available. For all of the channel-bound toxins investigated herein, a certain conformational flexibility was observed during the molecular dynamic simulations, which corresponds to their bioactivity. Our data suggest a similar binding mode of µ-PIIIA at KV1.6 and KV1.1, in which a plethora of hydrogen bonds are formed by the Arg and Lys residues within the α-helical core region of µ-PIIIA, with the central pore residues of the channel. Furthermore, the contribution of the K+ channel’s outer and inner pore loops with respect to the toxin binding. and how the subtype specificity is induced, were proposed. View Full-Text
Keywords: potassium channel; µ-conotoxins; µ-PIIIA; µ-SIIIA; µ-GIIIA; ion channel; toxin interactions potassium channel; µ-conotoxins; µ-PIIIA; µ-SIIIA; µ-GIIIA; ion channel; toxin interactions
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Kaufmann, D.; Tietze, A.A.; Tietze, D. In Silico Analysis of the Subtype Selective Blockage of KCNA Ion Channels through the µ-Conotoxins PIIIA, SIIIA, and GIIIA. Mar. Drugs 2019, 17, 180.

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