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Mar. Drugs 2017, 15(6), 164;

A Novel Lid-Covering Peptide Inhibitor of Nicotinic Acetylcholine Receptors Derived from αD-Conotoxin GeXXA

Department of Central Laboratory, Shanghai 10th People’s Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, NSW 2522, Australia
iHuman Institute, ShanghaiTech University, Shanghai 201210, China
School of Life Science and Technology, ShanghaiTech University, Shanghai 201219, China
Authors to whom correspondence should be addressed.
Academic Editor: Orazio Taglialatela-Scafati
Received: 24 April 2017 / Revised: 28 May 2017 / Accepted: 31 May 2017 / Published: 5 June 2017
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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. View Full-Text
Keywords: nAChR; conotoxin; αD-GeXXA; NTD; lid-covering nAChR; conotoxin; αD-GeXXA; NTD; lid-covering

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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.

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