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

Paul George, Ajay Abisheck; Heimer, Pascal; Leipold, Enrico; Schmitz, Thomas; Kaufmann, Desiree; Tietze, Daniel; Heinemann, Stefan H.; Imhof, Diana

doi:10.3390/md17070390

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

Ajay Abisheck Paul George

^1,†,

^1,†,

^2,†,

¹,

³,

⁴

and

Diana Imhof

^1,*

Pharmaceutical Biochemistry and Bioanalytics, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany

Department of Anesthesiology and Intensive Care, University of Lübeck, Ratzeburger Allee 160, D-23562 Lübeck, Germany

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 Na_V1.4, 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 Na_V1.4 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 Na_V1.4, 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

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MDPI and ACS Style

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. https://doi.org/10.3390/md17070390

AMA Style

Paul George AA, Heimer P, Leipold E, Schmitz T, Kaufmann D, Tietze D, Heinemann SH, Imhof D. Effect of Conformational Diversity on the Bioactivity of µ-Conotoxin PIIIA Disulfide Isomers. Marine Drugs. 2019; 17(7):390. https://doi.org/10.3390/md17070390

Chicago/Turabian Style

Paul George, Ajay A., Pascal Heimer, Enrico Leipold, Thomas Schmitz, Desiree Kaufmann, Daniel Tietze, Stefan H. Heinemann, and Diana Imhof. 2019. "Effect of Conformational Diversity on the Bioactivity of µ-Conotoxin PIIIA Disulfide Isomers" Marine Drugs 17, no. 7: 390. https://doi.org/10.3390/md17070390

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

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