Biophysics of Receptor/G-protein Interactions

受体/G 蛋白相互作用的生物物理学

基本信息

批准号：
8138391
负责人：
OLEG G KISSELEV
金额：
$ 27.37万
依托单位：
SAINT LOUIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8138391
关键词：
Allosteric Regulation Asthma Binding Biological Models Biophysics C-terminal Cell Communication Cell Surface Receptors Cell physiology Cells Chemicals Complex Coupled Data Disease Docking Drug Design Engineering Equilibrium Fluorescence Fluorescent Probes G-Protein-Coupled Receptors GTP-Binding Proteins Heart Heterotrimeric GTP-Binding Proteins Hormones Hydroxylamine Individual Knowledge Label Location Maps Marketing Membrane Modeling Molecular Molecular Conformation Monitor N-terminal NMR Spectroscopy Neurotransmitters Pattern Pharmaceutical Preparations Phototransduction Process Protein Subunits Radio Regulation Research Resolution Rhodopsin Role Route Series Signal Pathway Signal Transduction Site Spin Labels Testing Therapeutic Therapeutic Intervention Transducin Tryptophan Vision Disorders Work base dimer extracellular fighting insight ionization monomer protein activation protein function protein protein interaction public health research receptor receptor coupling research study response retinal rods sensory stimulus stoichiometry theories transmission process

项目摘要

DESCRIPTION (provided by applicant): Cell surface receptors coupled to the heterotrimeric GTP-binding proteins are universally responsible for the transmembrane transmission of extracellular messengers such as hormones, neurotransmitters and a variety of sensory stimuli. Because of this direct involvement in the regulation of the most crucial cellular functions, G-protein coupled receptors (GPCRs) are among the most important targets of therapeutic intervention. It's estimated that about 50% of drugs in use act on GPCRs. Thus, understanding of the receptor and the G- protein functions at the molecular level is among the highest priorities of public health research. Several competing models aim at describing the universal mechanism of G- protein activation by GPCRs, but none has presented compelling and conclusive experimental evidence so far. HYPOTHESIS: G-protein 23-subunit complex is a key molecular switch at the center of the gear-shift model of G-protein activation. We will test this hypothesis using the prototypical GPCR rhodopsin (R) and the G-protein transducin (Gt) responsible for phototransduction in retinal rod cells as a model system. Three interconnected Specific Aims will test various aspects of the hypothesis, such as questions of the molecular organization of the receptor- G-protein complex, the high-resolution picture of the receptor-G-protein interface, the mechanism of signal transfer from the receptor, and the roles of individual G- protein subunits, especially the G23 subunit complex, in this dynamic process. This project aims at understanding the universal principles underlying cell- to-cell communications and cellular responses to a variety of sensory stimuli. Several competing theories describing these basic molecular mechanisms will be tested to gain insights into the inner workings of cell surface receptor proteins and specific protein-protein interactions. Because almost half of all therapeutics on the market today target these signaling pathways, knowledge obtained as a result of these studies will be essential in new drug design and fighting a wide range of diseases such as heart problems, asthma and vision disorders.

描述（由申请人提供）：与异三聚体GTP结合蛋白结合的细胞表面受体是普遍负责细胞外信使的跨膜传播，例如激素，神经递质和各种感觉刺激。由于这种直接参与最关键的细胞功能的调节，G蛋白偶联受体（GPCR）是治疗干预的最重要靶标之一。据估计，大约50％的使用药物对GPCR进行了ACT。因此，对分子水平的受体和G蛋白功能的理解是公共卫生研究的最高优先事项之一。几个竞争模型旨在描述GPCR的G蛋白激活的通用机制，但迄今为止，没有一个曾提供令人信服的结论性实验证据。假设：G蛋白23亚基复合物是G蛋白激活齿轮移动模型中心的关键分子开关。我们将使用原型GPCR视紫红素（R）和负责视网膜杆细胞中光转导的GPCR Rhodopsin（R）和G蛋白转蛋白（GT）作为模型系统来检验这一假设。三个相互连接的特定目的将测试假设的各个方面，例如受体G蛋白复合物的分子组织问题，受体-G蛋白界面的高分辨率图片，信号转移的机制转移了从受体转移的机理，以及在这种动力学过程中的单个G-蛋白亚基的作用，尤其是单个G-蛋白质亚基的作用。该项目旨在理解细胞对电池通信的基本原理以及对各种感觉刺激的细胞反应。描述这些基本分子机制的几种竞争理论将进行测试，以了解细胞表面受体蛋白和特定蛋白质蛋白相互作用的内部起作用。由于当今市场上几乎一半的治疗疗法针对这些信号通路，因此这些研究获得的知识将在新药设计中至关重要，并与多种疾病（如心脏问题，哮喘和视力障碍）作斗争。