Role of CysI -CysIII Disulfide Bond on the Structure and Activity of α-Conotoxins at Human Neuronal Nicotinic Acetylcholine Receptors

ACS Omega
Nargis TabassumRilei Yu

Abstract

α-Conotoxins preferentially antagonize muscle and neuronal nicotinic acetylcholine receptors (nAChRs). Native α-conotoxins have two disulfide links, CI-CIII and CII-CIV, and owing to the inherent properties of disulfide bonds, α-conotoxins have been systematically engineered to improve their chemical and biological properties. In this study, we explored the possibility of simplifying the disulfide framework of α-conotoxins Vc1.1, BuIA, ImI, and AuIB, by introducing [C2H,C8F] modification to the CI-CIII bond. We therefore explored the possibility of using hydrophobic packing of standard amino acid side chains to replace disulfide bonds as an alternative strategy to nonnatural amino acid cross-links. The impact of CI-CIII disulfide bond replacement on the conformation of the α-conotoxins was investigated using molecular dynamics (MD) simulations and nuclear magnetic resonance chemical shift index study. Two-electrode voltage clamp techniques and MD simulations were used to study the impact of disulfide bond deletion on the activities of the peptides at human neuronal nAChRs. All disulfide-deleted variants except ImI[C2H,C8F] had reduced potency for inhibiting nAChRs. Our results suggest that the CI-CIII disulfide bond is importan...Continue Reading

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Citations

Aug 6, 2020·Database : the Journal of Biological Databases and Curation·Xiao LiRilei Yu
Mar 6, 2019·Marine Drugs·Rachael A MansbachS Gnanakaran
Jan 28, 2020·Journal of Medicinal Chemistry·Pan XuSulan Luo

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Methods Mentioned

BETA
nuclear magnetic resonance
NMR
electrophoresis

Software Mentioned

GraphPad Prism
Amber
BuIA
Clampfit
pCLAMP9
PropKa
Modeller
CcpNmr
PyMol

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