Chemical engineering and structural and pharmacological characterization of the alpha-scorpion toxin OD1

Durek, Thomas, Vetter, Irina, Wang, Ching-I Anderson, Motin, Leonid, Knapp, Oliver, Adams, David J., Lewis, Richard J. and Alewood, Paul F. (2013) Chemical engineering and structural and pharmacological characterization of the alpha-scorpion toxin OD1. ACS Chemical Biology, 8 6: 1215-1222. doi:10.1021/cb400012k


Author Durek, Thomas
Vetter, Irina
Wang, Ching-I Anderson
Motin, Leonid
Knapp, Oliver
Adams, David J.
Lewis, Richard J.
Alewood, Paul F.
Title Chemical engineering and structural and pharmacological characterization of the alpha-scorpion toxin OD1
Formatted title
Chemical engineering and structural and pharmacological characterization of the α-scorpion toxin OD1
Journal name ACS Chemical Biology   Check publisher's open access policy
ISSN 1554-8929
1554-8937
Publication date 2013-06-21
Sub-type Article (original research)
DOI 10.1021/cb400012k
Volume 8
Issue 6
Start page 1215
End page 1222
Total pages 8
Place of publication Washington, DC, United States
Publisher American Chemical Society
Collection year 2014
Language eng
Formatted abstract
Scorpion α-toxins are invaluable pharmacological tools for studying voltage-gated sodium channels, but few structure–function studies have been undertaken due to their challenging synthesis. To address this deficiency, we report a chemical engineering strategy based upon native chemical ligation. The chemical synthesis of α-toxin OD1 was achieved by chemical ligation of three unprotected peptide segments. A high resolution X-ray structure (1.8 Å) of synthetic OD1 showed the typical βαββ α-toxin fold and revealed important conformational differences in the pharmacophore region when compared with other α-toxin structures. Pharmacological analysis of synthetic OD1 revealed potent α-toxin activity (inhibition of fast inactivation) at Nav1.7, as well as Nav1.4 and Nav1.6. In addition, OD1 also produced potent β-toxin activity at Nav1.4 and Nav1.6 (shift of channel activation in the hyperpolarizing direction), indicating that OD1 might interact at more than one site with Nav1.4 and Nav1.6. Investigation of nine OD1 mutants revealed that three residues in the reverse turn contributed significantly to selectivity, with the triple OD1 mutant (D9K, D10P, K11H) being 40-fold more selective for Nav1.7 over Nav1.6, while OD1 K11V was 5-fold more selective for Nav1.6 than Nav1.7. This switch in selectivity highlights the importance of the reverse turn for engineering α-toxins with altered selectivity at Nav subtypes.
Keyword Gated sodium-channels
Androctonus-Aaustralis-hector
Odonthobuthus-doriae
Neurotoxin
Protein
Modulation
Activation
Mechanisms
Inhibition
Expression
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
Institute for Molecular Bioscience - Publications
 
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