A Novel Lid-Covering Peptide Inhibitor of Nicotinic Acetylcholine Receptors Derived from D-Conotoxin GeXXA
Yang, Longjin1; Tae, Han-Shen2; Fan, Zhou3,4; Shao, Xiaoxia1; Xu, Shaoqiong1; Zhao, Suwen3,4; Adams, David J.2; Wang, Chunguang1
2017-06
Source PublicationMARINE DRUGS
ISSN1660-3397
Volume15Issue:6
DOI10.3390/md15060164
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 D-conotoxin GeXXA was identified to inhibit nAChRs by binding at the top surface of the receptors, and the monomeric C-terminal domain (CTD) of D-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 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 D-GeXXA is a lid-covering nAChR inhibitor, displaying a novel inhibitory mechanism distinct from other allosteric ligands of nAChRs.
KeywordnAChR conotoxin D-GeXXA NTD lid-covering
Indexed BySCI
Language英语
Funding ProjectAustralian Research Council (ARC)[DP150103990]
WOS Research AreaPharmacology & Pharmacy
WOS SubjectChemistry, Medicinal
WOS IDWOS:000404526900019
PublisherMDPI AG
WOS KeywordBINDING-SITES ; THERAPEUTICS ; ANTAGONISTS ; HOMOLOG ; DOMAIN ; PAIN
Original Document TypeArticle
Corresponding AuthorAdams, David J. ; Wang, Chunguang
Citation statistics
Cited Times:3[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://kms.shanghaitech.edu.cn/handle/2MSLDSTB/2918
Collection生命科学与技术学院
iHuman研究所_PI研究组_赵素文组
生命科学与技术学院_硕士生
Corresponding AuthorAdams, David J.; Wang, Chunguang
Affiliation1.Tongji Univ, Sch Life Sci & Technol, Shanghai Peoples Hosp 10, Dept Cent Lab, Shanghai 200092, Peoples R China
2.Univ Wollongong, IHMRI, Wollongong, NSW 2522, Australia
3.ShanghaiTech Univ, iHuman Inst, Shanghai 201210, Peoples R China
4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201219, Peoples R China
Recommended Citation
GB/T 7714
Yang, Longjin,Tae, Han-Shen,Fan, Zhou,et al. A Novel Lid-Covering Peptide Inhibitor of Nicotinic Acetylcholine Receptors Derived from D-Conotoxin GeXXA[J]. MARINE DRUGS,2017,15(6).
APA Yang, Longjin.,Tae, Han-Shen.,Fan, Zhou.,Shao, Xiaoxia.,Xu, Shaoqiong.,...&Wang, Chunguang.(2017).A Novel Lid-Covering Peptide Inhibitor of Nicotinic Acetylcholine Receptors Derived from D-Conotoxin GeXXA.MARINE DRUGS,15(6).
MLA Yang, Longjin,et al."A Novel Lid-Covering Peptide Inhibitor of Nicotinic Acetylcholine Receptors Derived from D-Conotoxin GeXXA".MARINE DRUGS 15.6(2017).
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