3D Structure and mechanism of the alpha7 nicotinic acetylcholine receptor

α7烟碱乙酰胆碱受体的3D结构和机制

基本信息

批准号：
9233215
负责人：
Ryan E Hibbs
金额：
$ 35.02万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9233215
关键词：
Affect Affinity Agonist Alzheimer&apos s Disease Benchmarking Binding Biophysical Process Biophysics Brain Calcium Classification Complement Complex Cryoelectron Microscopy Data Data Set Disease Drug Design Electrons Electrophysiology (science)Engineering Equilibrium Fab Immunoglobulins Family Gated Ion Channel Generations Goals Gold Image Immunologics Individual Ion Channel Gating Ions Ligands Link Maps Mediating Medicine Mental Health Methods Molecular Molecular Conformation Movement Mutagenesis Nature Nervous System Physiology Neurodegenerative Disorders Neurons Neurotransmitters Nicotinic Receptors Oxides Parkinson Disease Pathway interactions Peripheral Nervous System Permeability Pharmacology Physiological Presynaptic Terminals Procedures Process Proteins Research Project Grants Resolution Rest Sampling Schizophrenia Structure Sum Testing Therapeutic Thermodynamics Time Work alpha-bungarotoxin receptor base blind college crosslink density desensitization design detector disulfide bond experimental study improved innovation insight ligand gated channel member nervous system disorder neurotransmission novel particle public health relevance receptor receptor binding receptor function reconstruction screening success therapeutic target three dimensional structure

项目摘要

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.

描述（由申请人提供）：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重要治疗靶点。这些五聚体配体门控离子通道是 Cys 环受体超家族的成员，可介导整个中枢和神经系统的快速神经传递。我们的目标是从生物物理学的角度阐明半胱氨酸环受体功能的一般原理，我们希望了解结合和作用的模式。药物调节、状态转变下的构象变化以及 nAChR 和更广泛的 Cys 环受体家族的离子渗透和选择性机制，这些目标的进展与更好地理解神经系统疾病和疾病的基本机制直接相关。在此，我们建议对同型五聚体 α7 烟碱受体亚型进行结构表征。α7 亚型是治疗精神分裂症、阿尔茨海默氏症和阿尔茨海默氏症的新靶点。与大多数配体门控通道一样，在激动剂持续存在的情况下，一旦配体解离，受体将恢复到静息状态。本文提出的工作目标是确定该受体的高分辨率结构。不同构象状态下的 α7 受体的比较将首次提供从静止到激活到脱敏的门控循环的结构研究。将辅以药理学和电生理学，以测试由结构产生的机制假设。我们提出的研究将有助于更好地理解受体功能的机制，并将为设计针对不同受体状态的α7化合物提供分子蓝图。