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

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 a...

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Autores principales: Yang, Longjin, Tae, Han-Shen, Fan, Zhou, Shao, Xiaoxia, Xu, Shaoqiong, Zhao, Suwen, Adams, David J., Wang, Chunguang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5484114/
https://www.ncbi.nlm.nih.gov/pubmed/28587231
http://dx.doi.org/10.3390/md15060164
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author Yang, Longjin
Tae, Han-Shen
Fan, Zhou
Shao, Xiaoxia
Xu, Shaoqiong
Zhao, Suwen
Adams, David J.
Wang, Chunguang
author_facet Yang, Longjin
Tae, Han-Shen
Fan, Zhou
Shao, Xiaoxia
Xu, Shaoqiong
Zhao, Suwen
Adams, David J.
Wang, Chunguang
author_sort Yang, Longjin
collection PubMed
description 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.
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spelling pubmed-54841142017-06-29 A Novel Lid-Covering Peptide Inhibitor of Nicotinic Acetylcholine Receptors Derived from αD-Conotoxin GeXXA Yang, Longjin Tae, Han-Shen Fan, Zhou Shao, Xiaoxia Xu, Shaoqiong Zhao, Suwen Adams, David J. Wang, Chunguang Mar Drugs Article 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. MDPI 2017-06-05 /pmc/articles/PMC5484114/ /pubmed/28587231 http://dx.doi.org/10.3390/md15060164 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Yang, Longjin
Tae, Han-Shen
Fan, Zhou
Shao, Xiaoxia
Xu, Shaoqiong
Zhao, Suwen
Adams, David J.
Wang, Chunguang
A Novel Lid-Covering Peptide Inhibitor of Nicotinic Acetylcholine Receptors Derived from αD-Conotoxin GeXXA
title A Novel Lid-Covering Peptide Inhibitor of Nicotinic Acetylcholine Receptors Derived from αD-Conotoxin GeXXA
title_full A Novel Lid-Covering Peptide Inhibitor of Nicotinic Acetylcholine Receptors Derived from αD-Conotoxin GeXXA
title_fullStr A Novel Lid-Covering Peptide Inhibitor of Nicotinic Acetylcholine Receptors Derived from αD-Conotoxin GeXXA
title_full_unstemmed A Novel Lid-Covering Peptide Inhibitor of Nicotinic Acetylcholine Receptors Derived from αD-Conotoxin GeXXA
title_short A Novel Lid-Covering Peptide Inhibitor of Nicotinic Acetylcholine Receptors Derived from αD-Conotoxin GeXXA
title_sort novel lid-covering peptide inhibitor of nicotinic acetylcholine receptors derived from αd-conotoxin gexxa
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5484114/
https://www.ncbi.nlm.nih.gov/pubmed/28587231
http://dx.doi.org/10.3390/md15060164
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