A Novel Lid-Covering Peptide Inhibitor of Nicotinic Acetylcholine Receptors Derived from αD-Conotoxin GeXXA
AbstractNicotinic 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. View Full-Text
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Yang, L.; Tae, H.-S.; Fan, Z.; Shao, X.; Xu, S.; Zhao, S.; Adams, D.J.; Wang, C. A Novel Lid-Covering Peptide Inhibitor of Nicotinic Acetylcholine Receptors Derived from αD-Conotoxin GeXXA. Mar. Drugs 2017, 15, 164.
Yang L, Tae H-S, Fan Z, Shao X, Xu S, Zhao S, Adams DJ, Wang C. A Novel Lid-Covering Peptide Inhibitor of Nicotinic Acetylcholine Receptors Derived from αD-Conotoxin GeXXA. Marine Drugs. 2017; 15(6):164.Chicago/Turabian Style
Yang, Longjin; Tae, Han-Shen; Fan, Zhou; Shao, Xiaoxia; Xu, Shaoqiong; Zhao, Suwen; Adams, David J.; Wang, Chunguang. 2017. "A Novel Lid-Covering Peptide Inhibitor of Nicotinic Acetylcholine Receptors Derived from αD-Conotoxin GeXXA." Mar. Drugs 15, no. 6: 164.
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