Structural Basis of Agonist Selectivity for Different nAChR Subtypes: Insights from Crystal Structures, Mutation Experiments and Molecular Simulations

Ruo-Xu      Gu; Yu-Qing      Zhong; Dong-Qing      Wei

doi:10.2174/138161211796355119

Abstract

Nicotinic acetylcholine receptors (nAChRs) are members of ligand gated ion channels (LGICs) which transduce chemical signal into electrical signal in neuron and neuromuscular junction. They are pentamerics which contain an extra-cellular domain (also known as ligand binding domain or LBD), a trans-membrane domain and a cytoplasmic domain (intra-cellular domain). Agonist binding to the extra-cellular domain invokes positive ion flux as well as action potential in neurons, muscle cells and endocrine cells whereas antagonist binding inhibits ion flux. There are various endogenous or exogenous compounds which behave as agonists or antagonists targeting nAChRs. During the last decades, the whole structure of muscle type nAChR as well as the crystal structures of acetylcholine-binding proteins (AChBPs) which are homologues of the nAChRs extra-cellular domain has been obtained. These structures, together with other studies including mutation experiments and molecular simulations, provide insights into both of the nAChR architecture and its agonist binding cavity. Our review gives detailed accounts of the recent progresses in order to gain insights into agonist selectivity for different nAChR subtypes.

Keywords: Nicotinic acetylcholine receptor, cationic pharmacophore, hydrogen bond, agonist selectivity, crystal structure, molecular simulation, pentamerics, antagonist, strychnine-sensitive, 5-hydroxytryptamine, cysteine, desensitized, schizophrenia, allosteric, disulfide, Van der Waals, hydrophobic, hydrophilic helix, molluscan, aromatic