Computational Determination of the Binding Mode of α-Conotoxin to Nicotinic Acetylcholine Receptor  

作　　者：TABASSUM Nargis YU Rilei JIANG Tao TABASSUM Nargis;YU Rilei;JIANG Tao(Key Laboratory of Marine Drugs of Chinese Ministry of Education, School of Medicine and Pharmacy,Ocean University of China, Qingdao 266003, P. R. China)

机构地区：[1]Key Laboratory of Marine Drugs of Chinese Ministry of Education, School of Medicine and Pharmacy,Ocean University of China, Qingdao 266003, P. R. China

出　　处：《Journal of Ocean University of China》2016年第6期1027-1033,共7页中国海洋大学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China (81502977 to Dr. Yu R. and 81373322 to Dr. Jiang T.);China Postdoctoral Science Foundation funded project (No.861505020050 for Dr. Yu R.);Special Foundation for Qingdao Basic Research Program (15-9-1-85-jch);Fundamental Research Funds for the Central Universities (No.841512007 for Dr. Yu R.)

摘　　要：Abstract Conotoxins belong to the large families of disulfide-rich peptide toxins from cone snail venom, and can act on a broad spectrum of ion channels and receptors. They are classified into different subtypes based on their targets. The a-conotoxins selectively inhibit the current of the nicotinic acetylcholine receptors. Because of their unique selectivity towards distinct nAChR subtypes, a-conotoxins become valuable tools in nAChR study. In addition to the X-ray structures of a-conotoxins in complex with acetyleholine-binding protein, a homolog of the nAChR ligand-binding domain, the high-resolution crystal structures of the extracellular domain of the al and a9 subunits are also obtained. Such structures not only revealed the details of the configuration of nAChR, but also provided higher sequence identity templates for modeling the binding modes of a-conotoxins to nAChR. This mini-review summarizes recent modeling studies for the determination of the binding modes of a-conotoxins to nAChR. As there are not crystal structures of the nAChR in complex with conotoxins, computational modeling in combination of mutagenesis data is expected to reveal the molecular recognition mechanisms that govern the interactions between a-conotoxins and nAChR at molecular level. An accurate determination of the binding modes of a-conotoxins on AChRs allows rational design of a-conotoxin analogues with improved potency or selectivity to nAChRs.Conotoxins belong to the large families of disulfide-rich peptide toxins from cone snail venom, and can act on a broad spectrum of ion channels and receptors. They are classified into different subtypes based on their targets. The α-conotoxins selectively inhibit the current of the nicotinic acetylcholine receptors. Because of their unique selectivity towards distinct n ACh R subtypes, α-conotoxins become valuable tools in n ACh R study. In addition to the X-ray structures of α-conotoxins in complex with acetylcholine-binding protein, a homolog of the n ACh R ligand-binding domain, the high-resolution crystal structures of the extracellular domain of the α1 and α9 subunits are also obtained. Such structures not only revealed the details of the configuration of n ACh R, but also provided higher sequence identity templates for modeling the binding modes of α-conotoxins to n ACh R. This mini-review summarizes recent modeling studies for the determination of the binding modes of α-conotoxins to n ACh R. As there are not crystal structures of the n ACh R in complex with conotoxins, computational modeling in combination of mutagenesis data is expected to reveal the molecular recognition mechanisms that govern the interactions between α-conotoxins and n ACh R at molecular level. An accurate determination of the binding modes of α-conotoxins on ACh Rs allows rational design of α-conotoxin analogues with improved potency or selectivity to n ACh Rs.

关 键 词：Nicotinic acetylcholine receptor a-conotoxin acetylcholine binding protein DOCKING homology modeling moleculardynamics simulation mutational energy 

分 类 号：Q51[生物学—生物化学]