烟碱激动剂
乙酰胆碱受体
生物物理学
α-4β-2烟碱受体
变构调节
烟碱乙酰胆碱受体
化学
半胱氨酸环受体
乙酰胆碱
受体
配体门控离子通道
离子通道
尼古丁
门控
生物化学
细胞生物学
生物
药理学
神经科学
作者
Claudio L. Morales-Pérez,Colleen Noviello,Ryan Hibbs
标识
DOI:10.1016/j.bpj.2016.11.1735
摘要
Nicotinic acetylcholine receptors are ligand gated ion channels that mediate fast chemical neurotransmission at the neuromuscular junction and play diverse signaling roles in the central nervous system. Here we describe a biochemical approach for characterization of subunit stoichiometry in heteromeric membrane proteins and present the first X-ray crystal structure of a nicotinic receptor. The α4β2 nicotinic receptor is the most abundant receptor subtype in the brain, is the principal target in nicotine addiction and its dysfunction is associated with familial epilepsy. The structure of the receptor in complex with the agonist nicotine reveals principles of ligand selectivity among different classes of subunit interfaces in the heteropentameric assembly. The receptor is stabilized by nicotine in a non-conducting, desensitized conformation. The constriction point in the permeation pathway is formed at the selectivity filter, located at the cytosolic end of the pore. The desensitized state of this channel provides a distinct structural reference point in the allosteric gating cycle of the larger Cys-loop receptor superfamily.
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