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A novel lid-covering peptide inhibitor of nicotinic acetylcholine receptors derived from αd-conotoxin GeXXA

Journal Article


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Abstract


  • Nicotinic acetylcholine receptors (nAChRs) play a fundamental role in nervous signal transmission, therefore various antagonists and agonists are highly desired to explore the structure and function of nAChRs. Recently, a novel dimeric αD-conotoxin GeXXA was identified to inhibit nAChRs by binding at the top surface of the receptors, and the monomeric C-terminal domain (CTD) of αD-GeXXA retains some inhibitory activity. In this study, the internal dimeric N-terminal domain (NTD) of this conopeptide was further investigated. We first developed a regio-selective protection strategy to chemically prepare the anti-parallel dimeric NTD, and found that the isolated NTD part of GeXXA possesses the nAChR-inhibitory activity, the subtype-dependence of which implies a preferred binding of NTD to the β subunits of nAChR. Deletion of the NTD N-terminal residues did not affect the activity of NTD, indicating that the N-terminus is not involved in the interaction with nAChRs. By optimizing the sequence of NTD, we obtained a fully active single-chain cyclic NTD, based on which 4 Arg residues were found to interact with nAChRs. These results demonstrate that the NTD part of αD-GeXXA is a "lid-covering" nAChR inhibitor, displaying a novel inhibitory mechanism distinct from other allosteric ligands of nAChRs.

UOW Authors


  •   Yang, Longjin (external author)
  •   Tae, Han Shen
  •   Fan, Zhou (external author)
  •   Shao, Xiaoxia (external author)
  •   Xu, Shaoqiong (external author)
  •   Zhao, Suwen (external author)
  •   Adams, David
  •   Wang, Chunguang (external author)

Publication Date


  • 2017

Citation


  • Yang, L., Tae, H., Fan, Z., Shao, X., Xu, S., Zhao, S., Adams, D. J. & Wang, C. (2017). A novel lid-covering peptide inhibitor of nicotinic acetylcholine receptors derived from αd-conotoxin GeXXA. Marine Drugs, 15 (6),

Scopus Eid


  • 2-s2.0-85020839527

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=2127&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/1101

Volume


  • 15

Issue


  • 6

Place Of Publication


  • Switzerland

Abstract


  • Nicotinic acetylcholine receptors (nAChRs) play a fundamental role in nervous signal transmission, therefore various antagonists and agonists are highly desired to explore the structure and function of nAChRs. Recently, a novel dimeric αD-conotoxin GeXXA was identified to inhibit nAChRs by binding at the top surface of the receptors, and the monomeric C-terminal domain (CTD) of αD-GeXXA retains some inhibitory activity. In this study, the internal dimeric N-terminal domain (NTD) of this conopeptide was further investigated. We first developed a regio-selective protection strategy to chemically prepare the anti-parallel dimeric NTD, and found that the isolated NTD part of GeXXA possesses the nAChR-inhibitory activity, the subtype-dependence of which implies a preferred binding of NTD to the β subunits of nAChR. Deletion of the NTD N-terminal residues did not affect the activity of NTD, indicating that the N-terminus is not involved in the interaction with nAChRs. By optimizing the sequence of NTD, we obtained a fully active single-chain cyclic NTD, based on which 4 Arg residues were found to interact with nAChRs. These results demonstrate that the NTD part of αD-GeXXA is a "lid-covering" nAChR inhibitor, displaying a novel inhibitory mechanism distinct from other allosteric ligands of nAChRs.

UOW Authors


  •   Yang, Longjin (external author)
  •   Tae, Han Shen
  •   Fan, Zhou (external author)
  •   Shao, Xiaoxia (external author)
  •   Xu, Shaoqiong (external author)
  •   Zhao, Suwen (external author)
  •   Adams, David
  •   Wang, Chunguang (external author)

Publication Date


  • 2017

Citation


  • Yang, L., Tae, H., Fan, Z., Shao, X., Xu, S., Zhao, S., Adams, D. J. & Wang, C. (2017). A novel lid-covering peptide inhibitor of nicotinic acetylcholine receptors derived from αd-conotoxin GeXXA. Marine Drugs, 15 (6),

Scopus Eid


  • 2-s2.0-85020839527

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=2127&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/1101

Volume


  • 15

Issue


  • 6

Place Of Publication


  • Switzerland