Paul George, Ajay Abisheck ; 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.
In: Marine Drugs, 17 (7)
doi: 10.3390/md17070390
Artikel, Bibliographie
Dies ist die neueste Version dieses Eintrags.
Kurzbeschreibung (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.
| Typ des Eintrags: | Artikel |
|---|---|
| Erschienen: | 2019 |
| Autor(en): | Paul George, Ajay Abisheck ; Heimer, Pascal ; Leipold, Enrico ; Schmitz, Thomas ; Kaufmann, Desiree ; Tietze, Daniel ; Heinemann, Stefan H. ; Imhof, Diana |
| Art des Eintrags: | Bibliographie |
| Titel: | Effect of conformational diversity on the bioactivity of µ-conotoxin PIIIA disulfide isomers |
| Sprache: | Englisch |
| Publikationsjahr: | 2019 |
| Ort: | Basel |
| Verlag: | MDPI |
| Titel der Zeitschrift, Zeitung oder Schriftenreihe: | Marine Drugs |
| Jahrgang/Volume einer Zeitschrift: | 17 |
| (Heft-)Nummer: | 7 |
| Kollation: | 18 Seiten |
| DOI: | 10.3390/md17070390 |
| Zugehörige Links: | |
| Kurzbeschreibung (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. |
| Freie Schlagworte: | µ-conotoxin, PIIIA, voltage-gated sodium channel, disulfide connectivity, peptide folding, electrophysiology, molecular docking, molecular dynamics |
| Sachgruppe der Dewey Dezimalklassifikatin (DDC): | 500 Naturwissenschaften und Mathematik > 540 Chemie 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin, Gesundheit |
| Fachbereich(e)/-gebiet(e): | 07 Fachbereich Chemie 07 Fachbereich Chemie > Eduard Zintl-Institut > Fachgebiet Physikalische Chemie |
| Hinterlegungsdatum: | 16 Jan 2024 07:44 |
| Letzte Änderung: | 16 Jan 2024 07:44 |
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| Suche nach Titel in: | TUfind oder in Google |
Verfügbare Versionen dieses Eintrags
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Effect of Conformational Diversity on the Bioactivity of µ-Conotoxin PIIIA Disulfide Isomers. (deposited 15 Jan 2024 13:53)
- Effect of conformational diversity on the bioactivity of µ-conotoxin PIIIA disulfide isomers. (deposited 16 Jan 2024 07:44) [Gegenwärtig angezeigt]
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