Mechanism of interactions betweenα-conotoxin RegIIA and carbohydrates at the humanα3β4 nicotinic acetylcholine receptor  

作　　者：Meiling Zheng Han-Shen Tae Liang Xue Tao Jiang Rilei Yu 

机构地区：[1]Molecular Synthesis Center&Key Laboratory of Marine Drugs,Ministry of Education,School of Medicine and Pharmacy,Ocean University of China,Qingdao,266003,China [2]Innovation Platform of Marine Drug Screening&Evaluation,Pilot National Laboratory for Marine Science and Technology(Qingdao),Qingdao,266100,China [3]Illawarra Health and Medical Research Institute(IHMRI),University of Wollongong,Wollongong,NSW,2522,Australia [4]Laboratory for Marine Drugs and Bioproducts,Pilot National Laboratory for Marine Science and Technology(Qingdao),Qingdao,266003,China

出　　处：《Marine Life Science & Technology》2022年第1期98-105,共8页海洋生命科学与技术（英文）

基　　金：supported by the National Key Research and Development Program(2019YFC0312601);the grant from the Fundamental Research Funds for the Central Universities(201762011 and 201941012);National Natural Science Foundation of China(NSFC)(No.81502977 and 41830535);an Australian Research Council(ARC)Discovery Project Grant(DP150103990 awarded to Prof D.J.Adams)。

摘　　要：Conotoxins are marine peptide toxins from marine cone snails.Theα-conotoxin RegIIA can selectively act on human(h)α3β4 nicotinic acetylcholine receptor(nAChR),and is an important lead for drug development.The high-resolution cryo-electron microscopy structure of theα3β4 nAChR demonstrates several carbohydrates are located near the orthosteric binding sites,which may affectα-conotoxin binding.Oligosaccharide chains can modify the physical and chemical properties of proteins by changing the conformation,hydrophobicity,quality and size of the protein.The purpose of this study is to explore the effect of oligosaccharide chains on the binding modes and activities of RegIIA and its derivatives at hα3β4 nAChRs.Through computational simulations,we designed and synthesized RegIIA mutants at position 14 to explore the importance of residue H14 to the activity of the peptide.Molecular dynamics simulations suggest that the oligosaccharide chains affect the binding of RegIIA at the hα3β4 nAChR through direct interactions with H14 and by affecting the C-loop conformation of the binding sites.Electrophysiology studies on H14 analogues suggest that in addition to forming direct interactions with the carbohydrates,the residue might play an important role in maintaining the conformation of the peptide.Overall,this study further clarifies the structure–activity relationship ofα-conotoxin RegIIA at the hα3β4 nAChR and,also provides important experimental and theoretical basis for the development of new peptide drugs.

关 键 词：Oligosaccharide chains NACHR CONOTOXIN Action mechanism 

分 类 号：Q95[生物学—动物学]