Biophsyics of Receptor/G-protein Interactions

与异源三聚体GTP结合蛋白偶联的细胞表面受体普遍负责细胞内ATP的释放。 细胞外信使如激素、神经递质和感觉神经递质的跨膜传递 刺激。由于G蛋白直接参与调节最重要的细胞功能， 偶联受体（GPCR）是治疗干预的最重要的靶点。据估计 大约50%的药物作用于GPCR。因此，对受体和G蛋白的理解 分子水平上的功能是公共卫生研究的最高优先事项之一。 几种竞争模型旨在描述GPCR激活G蛋白的通用机制， 但迄今为止，没有一个人提出令人信服的结论性实验证据。假设：G蛋白 β-γ亚基复合物是G蛋白换档模型中心的关键分子开关 activation.我们将使用原型GPCR视紫红质（R）和G蛋白来检验这一假设。 转导素（Gt）作为模型系统负责视网膜视杆细胞中的光转导。四个相互关联 具体目标将测试假设的各个方面，如分子组织的问题。 受体-G蛋白复合物，受体-G蛋白界面的高分辨率图片， 受体信号传递的机制，以及单个G蛋白亚基的作用，特别是 G蛋白β-γ亚基复合物，在这个动态过程中。

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 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 beta-gamma 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. Four 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 G-protein beta-gamma subunit complex, in this dynamic process.