Effect of Conformational Diversity on the Bioactivity of µ-Conotoxin PIIIA Disulfide Isomers
AbstractCyclic 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
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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.
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.Chicago/Turabian Style
Paul George, Ajay A.; Heimer, Pascal; Leipold, Enrico; Schmitz, Thomas; Kaufmann, Desiree; Tietze, Daniel; Heinemann, Stefan H.; Imhof, Diana. 2019. "Effect of Conformational Diversity on the Bioactivity of µ-Conotoxin PIIIA Disulfide Isomers." Mar. Drugs 17, no. 7: 390.
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