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Stoichiometry dependent inhibition of rat α3β4 nicotinic acetylcholine receptor by the ribbon isomer of α-conotoxin AuIB

Journal Article


Abstract


  • The ribbon isomer of α-conotoxin AuIB has 10-fold greater potency than the wild-type globular isomer at inhibiting nicotinic acetylcholine receptors (nAChRs) in rat parasympathetic neurons, and unlike its globular isoform, ribbon AuIB only targets a specific stoichiometry of the α3β4 nAChR subtype. Previous electrophysiological recordings of AuIB indicated that ribbon AuIB binds to the α3(+)α3(−) interface within the nAChR extracellular domain, which is displayed by the (α3)3(β4)2stoichiometry but not by (α3)2(β4)3. This specificity for a particular stoichiometry is remarkable and suggests that ribbon isoforms of α-conotoxins might have great potential in drug design. In this study, we investigated the binding mode and structure-activity relationships of ribbon AuIB using a combination of molecular modeling and electrophysiology recording to determine the features that underpin its selectivity. An alanine scan showed that positions 4 and 9 of ribbon AuIB are the main determinants of the interaction with (α3)3(β4)2nAChR. Our computational models indicate that the first loop of ribbon AuIB binds in the “aromatic box” of the acetylcholine orthosteric binding site, similar to that of globular AuIB. In contrast, the second loop and the termini of the ribbon isomer have different orientations and interactions in the binding sites to those of the globular isomer. The structure-activity relationships reported herein should be useful to design peptides displaying a ribbon α-conotoxin scaffold for inhibition of nAChR subtypes that have hitherto been difficult to selectively target.

UOW Authors


  •   Wu, Xiaosa (external author)
  •   Tae, Han Shen
  •   Huang, Yen-Hua (external author)
  •   Adams, David
  •   Craik, David J. (external author)
  •   Kaas, Quentin (external author)

Publication Date


  • 2018

Citation


  • Wu, X., Tae, H., Huang, Y., Adams, D. J., Craik, D. J. & Kaas, Q. (2018). Stoichiometry dependent inhibition of rat α3β4 nicotinic acetylcholine receptor by the ribbon isomer of α-conotoxin AuIB. Biochemical Pharmacology, 155 288-297.

Scopus Eid


  • 2-s2.0-85050149649

Number Of Pages


  • 9

Start Page


  • 288

End Page


  • 297

Volume


  • 155

Place Of Publication


  • United States

Abstract


  • The ribbon isomer of α-conotoxin AuIB has 10-fold greater potency than the wild-type globular isomer at inhibiting nicotinic acetylcholine receptors (nAChRs) in rat parasympathetic neurons, and unlike its globular isoform, ribbon AuIB only targets a specific stoichiometry of the α3β4 nAChR subtype. Previous electrophysiological recordings of AuIB indicated that ribbon AuIB binds to the α3(+)α3(−) interface within the nAChR extracellular domain, which is displayed by the (α3)3(β4)2stoichiometry but not by (α3)2(β4)3. This specificity for a particular stoichiometry is remarkable and suggests that ribbon isoforms of α-conotoxins might have great potential in drug design. In this study, we investigated the binding mode and structure-activity relationships of ribbon AuIB using a combination of molecular modeling and electrophysiology recording to determine the features that underpin its selectivity. An alanine scan showed that positions 4 and 9 of ribbon AuIB are the main determinants of the interaction with (α3)3(β4)2nAChR. Our computational models indicate that the first loop of ribbon AuIB binds in the “aromatic box” of the acetylcholine orthosteric binding site, similar to that of globular AuIB. In contrast, the second loop and the termini of the ribbon isomer have different orientations and interactions in the binding sites to those of the globular isomer. The structure-activity relationships reported herein should be useful to design peptides displaying a ribbon α-conotoxin scaffold for inhibition of nAChR subtypes that have hitherto been difficult to selectively target.

UOW Authors


  •   Wu, Xiaosa (external author)
  •   Tae, Han Shen
  •   Huang, Yen-Hua (external author)
  •   Adams, David
  •   Craik, David J. (external author)
  •   Kaas, Quentin (external author)

Publication Date


  • 2018

Citation


  • Wu, X., Tae, H., Huang, Y., Adams, D. J., Craik, D. J. & Kaas, Q. (2018). Stoichiometry dependent inhibition of rat α3β4 nicotinic acetylcholine receptor by the ribbon isomer of α-conotoxin AuIB. Biochemical Pharmacology, 155 288-297.

Scopus Eid


  • 2-s2.0-85050149649

Number Of Pages


  • 9

Start Page


  • 288

End Page


  • 297

Volume


  • 155

Place Of Publication


  • United States