δ-Conotoxins synthesized using an acid-cleavable solubility tag approach reveal key structural determinants for NaV subtype selectivity
| Autor: | Hubert François Gaertner, Philippe Favreau, Marianne Paolini-Bertrand, Daniel Biass, Steve Peigneur, Aude Violette, Oliver Hartley, Jan Tytgat, Reto Stöcklin |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Voltage-Gated Sodium Channels
ddc:616.07 Biochemistry Chemical synthesis Xenopus laevis Protein Isoforms Conotoxin Disulfides Peptide sequence Chromatography High Pressure Liquid biology Chemistry Peptide chemical synthesis Molecular Pharmacology musculoskeletal system 3. Good health Protein Structure and Folding Female Ion Channel Gating Conotoxins/chemical synthesis/chemistry/pharmacology Conus Snail/chemistry Spectrometry Mass Electrospray Ionization Stereochemistry Oocytes/drug effects/metabolism/physiology Molecular Sequence Data complex mixtures Protein Isoforms/genetics/physiology Structure-Activity Relationship Ion Channel Gating/drug effects/genetics/physiology Peptide Fragments/chemical synthesis/chemistry/pharmacology parasitic diseases Structure–activity relationship Animals Amino Acid Sequence ddc:576 Molecular Biology Ion channel Voltage-Gated Sodium Channels/genetics/physiology Dose-Response Relationship Drug fungi Conus Snail Cell Biology Acids/chemistry biology.organism_classification Peptide Fragments nervous system Solubility Conus consors Oocytes Conotoxins Acids Disulfides/chemistry |
| Zdroj: | Journal of Biological Chemistry, Vol. 289, No 51 (2014) pp. 35341-50 The Journal of biological chemistry |
| ISSN: | 0021-9258 |
| Popis: | Conotoxins are venom peptides from cone snails with multiple disulfide bridges that provide a rigid structural scaffold. Typically acting on ion channels implicated in neurotransmission, conotoxins are of interest both as tools for pharmacological studies and as potential new medicines. δ-Conotoxins act by inhibiting inactivation of voltage-gated sodium channels (Nav). Their pharmacology has not been extensively studied because their highly hydrophobic character makes them difficult targets for chemical synthesis. Here we adopted an acid-cleavable solubility tag strategy that facilitated synthesis, purification, and directed disulfide bridge formation. Using this approach we readily produced three native δ-conotoxins from Conus consors plus two rationally designed hybrid peptides. We observed striking differences in Nav subtype selectivity across this group of compounds, which differ in primary structure at only three positions: 12, 23, and 25. Our results provide new insights into the structure-activity relationships underlying the Nav subtype selectivity of δ-conotoxins. Use of the acid-cleavable solubility tag strategy should facilitate synthesis of other hydrophobic peptides with complex disulfide bridge patterns. |
| Databáze: | OpenAIRE |
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