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

作者：Yang, Longjin; Tae, Han-Shen; Fan, Zhou; Shao, Xiaoxia; Xu, Shaoqiong; Zhao, Suwen; Adams, David J.^*; Wang, Chunguang^*

来源：Marine Drugs, 2017, 15(6): 164.

DOI：10.3390/md15060164

• nAChR
• conotoxin
• D-GeXXA
• NTD
• lid-covering

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 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.

• 出版日期2017-6
• 单位上海科技大学; 同济大学