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Mar. Drugs 2017, 15(6), 164; doi:10.3390/md15060164

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

1
Department of Central Laboratory, Shanghai 10th People’s Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
2
Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, NSW 2522, Australia
3
iHuman Institute, ShanghaiTech University, Shanghai 201210, China
4
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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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. View Full-Text
Keywords: nAChR; conotoxin; αD-GeXXA; NTD; lid-covering nAChR; conotoxin; αD-GeXXA; NTD; lid-covering
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MDPI and ACS Style

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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