3D Structure and mechanism of the alpha7 nicotinic acetylcholine receptor

 描述（由申请方提供）：神经元烟碱乙酰胆碱受体（nAChR）是精神健康和神经退行性疾病的基本治疗靶点。这些五聚体配体门控离子通道是Cys环受体超家族的成员，其介导整个中枢和外周神经系统的快速神经传递。我们的目的是阐明Cys环受体功能的一般原则。从生物物理学的角度来看，我们希望了解药理学试剂的结合和调制模式，潜在的状态转换的构象变化，以及nAChR和更广泛的Cys环受体家族的离子渗透和选择性机制。实现这些目标的进展直接关系到更好地理解神经系统疾病的基本机制和治疗它们的治疗方法的设计。在这里，我们提出的结构特征的同型五聚体α7烟碱受体亚型。α7亚型是治疗精神分裂症、阿尔茨海默病和帕金森病的新靶点。像大多数配体门控通道一样，在激动剂持续存在下，α7受体迅速脱敏.一旦配体解离，受体就会恢复到静息状态。本文提出的工作目标是确定不同构象状态下α7受体的高分辨率结构。比较α7在其三种主要功能状态下的结构，将首次允许从结构上观察从静息到激活再到脱敏的门控周期。结构研究将辅以药理学和电生理学，以测试结构产生的机制假设。我们提出的研究将导致更好地理解受体功能的机制，并将为设计对不同受体状态具有选择性的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.