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Role of Cys(I)-Cys(III) Disulfide Bond on the Structure and Activity of α-Conotoxins at Human Neuronal Nicotinic Acetylcholine Receptors

Journal Article


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 important to stabilize the secondary structure of α-conotoxins as well as their interaction with neuronal nAChR targets. Results from this study enrich our understanding of the function of the CI–CIII disulfide bond and are useful in guiding future structural engineering of the α-conotoxins.

UOW Authors


  •   Tabassum, Nargis (external author)
  •   Tae, Han Shen
  •   Jia, Xinying (external author)
  •   Kaas, Quentin (external author)
  •   Jiang, Tao (external author)
  •   Adams, David
  •   Yu, Rilei (external author)

Publication Date


  • 2017

Citation


  • Tabassum, N., Tae, H., Jia, X., Kaas, Q., Jiang, T., Adams, D. J. & Yu, R. (2017). Role of Cys(I)-Cys(III) Disulfide Bond on the Structure and Activity of α-Conotoxins at Human Neuronal Nicotinic Acetylcholine Receptors. ACS Omega, 2 (8), 4621-4631.

Number Of Pages


  • 10

Start Page


  • 4621

End Page


  • 4631

Volume


  • 2

Issue


  • 8

Place Of Publication


  • United States

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 important to stabilize the secondary structure of α-conotoxins as well as their interaction with neuronal nAChR targets. Results from this study enrich our understanding of the function of the CI–CIII disulfide bond and are useful in guiding future structural engineering of the α-conotoxins.

UOW Authors


  •   Tabassum, Nargis (external author)
  •   Tae, Han Shen
  •   Jia, Xinying (external author)
  •   Kaas, Quentin (external author)
  •   Jiang, Tao (external author)
  •   Adams, David
  •   Yu, Rilei (external author)

Publication Date


  • 2017

Citation


  • Tabassum, N., Tae, H., Jia, X., Kaas, Q., Jiang, T., Adams, D. J. & Yu, R. (2017). Role of Cys(I)-Cys(III) Disulfide Bond on the Structure and Activity of α-Conotoxins at Human Neuronal Nicotinic Acetylcholine Receptors. ACS Omega, 2 (8), 4621-4631.

Number Of Pages


  • 10

Start Page


  • 4621

End Page


  • 4631

Volume


  • 2

Issue


  • 8

Place Of Publication


  • United States