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（由适用提供）：神经元烟碱乙酰胆碱受体（NACHRS）是心理健康和神经退行性疾病的必要治疗靶标。这些五聚体门控的离子通道是Cys-Loop受体超家族的成员，它介导了整个中央和周围神经系统的快速神经传递。我们旨在阐明CYS-LOOP受体功能的基础一般原则。从生物物理的角度来看，我们想了解药物的结合和调节模式，构象变化的状态过渡的基础变化以及NACHR和更广泛的Cys-loop受体家族中离子渗透和选择性的机制。朝着这些目标中的每个目标的进步直接与对神经系统疾病的基本机制的更好理解以及治疗方法的设计有关。在这里，我们建议在结构上表征同型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病的新目标。像大多数配体通道一样，在激动剂的持续存在下，α7受体迅速脱敏。一旦配体解离，接收器将返回静止状态。这里提出的工作的目的是确定不同会议状态下α7受体的高分辨率结构。在其三个主要功能状态中的α7结构的比较将允许第一次允许从静止到激活再到脱敏的门控循环的结构视图。结构研究将通过药理学和电生理学完成，以测试由结构产生的机械假设。我们提出的研究将使人们对受体功能的机制有更好的了解，并将为针对不同受体状态选择性的α7化合物设计提供分子蓝图。