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Effect of Conformational Diversity on the Bioactivity of µ-Conotoxin PIIIA Disulfide Isomers

1
Pharmaceutical Biochemistry and Bioanalytics, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany
2
Department of Anesthesiology and Intensive Care, University of Lübeck, Ratzeburger Allee 160, D-23562 Lübeck, Germany
3
Eduard Zintl Institute of Inorganic and Physical Chemistry, Darmstadt University of Technology, Alarich-Weiss-Str. 4, D-64287 Darmstadt, Germany
4
Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena and Jena University Hospital, Hans-Knöll-Str. 2, D-07745 Jena, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Mar. Drugs 2019, 17(7), 390; https://doi.org/10.3390/md17070390
Received: 5 June 2019 / Revised: 21 June 2019 / Accepted: 25 June 2019 / Published: 2 July 2019
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Abstract

Cyclic µ-conotoxin PIIIA, a potent blocker of skeletal muscle voltage-gated sodium channel NaV1.4, is a 22mer peptide stabilized by three disulfide bonds. Combining electrophysiological measurements with molecular docking and dynamic simulations based on NMR solution structures, we investigated the 15 possible 3-disulfide-bonded isomers of µ-PIIIA to relate their blocking activity at NaV1.4 to their disulfide connectivity. In addition, three µ-PIIIA mutants derived from the native disulfide isomer, in which one of the disulfide bonds was omitted (C4-16, C5-C21, C11-C22), were generated using a targeted protecting group strategy and tested using the aforementioned methods. The 3-disulfide-bonded isomers had a range of different conformational stabilities, with highly unstructured, flexible conformations with low or no channel-blocking activity, while more constrained molecules preserved 30% to 50% of the native isomer’s activity. This emphasizes the importance and direct link between correct fold and function. The elimination of one disulfide bond resulted in a significant loss of blocking activity at NaV1.4, highlighting the importance of the 3-disulfide-bonded architecture for µ-PIIIA. µ-PIIIA bioactivity is governed by a subtle interplay between an optimally folded structure resulting from a specific disulfide connectivity and the electrostatic potential of the conformational ensemble. View Full-Text
Keywords: µ-conotoxin; PIIIA; voltage-gated sodium channel; disulfide connectivity; peptide folding; electrophysiology; molecular docking; molecular dynamics µ-conotoxin; PIIIA; voltage-gated sodium channel; disulfide connectivity; peptide folding; electrophysiology; molecular docking; molecular dynamics
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Paul George, A.A.; Heimer, P.; Leipold, E.; Schmitz, T.; Kaufmann, D.; Tietze, D.; Heinemann, S.H.; Imhof, D. Effect of Conformational Diversity on the Bioactivity of µ-Conotoxin PIIIA Disulfide Isomers. Mar. Drugs 2019, 17, 390.

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