3D Structure and mechanism of the alpha7 nicotinic acetylcholine receptor

 描述(由申请人提供)：神经元烟碱型乙酰胆碱受体(NAChRs)是精神健康和神经退行性疾病的基本治疗靶点。这些五聚体配基门控离子通道是Cys-loop受体超家族的成员，在中枢和外周神经系统中介导快速的神经传递。我们的目标是阐明Cys-loop受体功能的一般原理。从生物物理学的角度，我们想要了解药物的结合和调节模式，状态转变背后的构象变化，以及nAChR和更广泛的Cys-loop受体家族中离子渗透和选择性的机制。实现这些目标的进展与更好地了解神经系统疾病的基本机制和设计治疗方法直接相关。在这里，我们建议从结构上表征α7烟碱受体亚型。α7亚型是治疗精神分裂症、阿尔茨海默氏症和帕金森氏症的新靶点。像大多数配基门控通道一样，在激动剂的持续存在下，α7受体迅速脱敏。一旦配体解离，受体就会回到静息状态。这项工作的目标是确定α7受体在不同构象状态下的高分辨结构。对α7在其三种主要功能状态下的结构进行比较，将首次允许从静止到激活再到失敏的门控周期的结构视图。结构研究将与药理学和电生理学相辅相成，以测试从结构中产生的机械假说。我们提出的研究将有助于更好地理解受体的作用机制，并将为设计选择性地针对不同受体状态的α7化合物提供分子蓝图。

 DESCRIPTION (provided by applicant): Neuronal nicotinic acetylcholine receptors (nAChRs) are essential therapeutic targets for mental health and neurodegenerative disorders. These pentameric ligand-gated ion channels are members of the Cys-loop receptor superfamily, which mediate fast neurotransmission throughout the central and peripheral nervous systems. We aim to elucidate general principles underlying Cys-loop receptor function. From a biophysical perspective, we want to understand modes of binding and modulation by pharmacological agents, conformational changes underlying state transitions, and mechanisms of ion permeation and selectivity in the nAChR and broader Cys-loop receptor family. Progress toward each of these goals is directly linked to a better understanding of basic mechanisms of nervous system disorders and the design of therapeutics to treat them. Here we propose to structurally characterize the homopentameric α7 nicotinic receptor subtype. The α7 subtype is a novel target in treating schizophrenia, Alzheimer's and Parkinson's diseases. Like most ligand- gated channels, in the continued presence of agonist the α7 receptor quickly desensitizes. Once ligand dissociates, the receptor will return to the resting state. The goal of the work proposed here is to determine high resolution structures of the α7 receptor in different conformational states. Comparison of the α7 structures in its three principal functional states will allow, for te first time, a structural view of the gating cycle from resting to activated to desensitized. The structural studies will be complemented with pharmacology and electrophysiology to test mechanistic hypotheses that arise from the structures. Our proposed studies will lead to a better understanding of the mechanisms of receptor function and will provide a molecular blueprint for design of α7 compounds selective for different receptor states.