PROBING RECEPTOR STRUCTURES WITH UNNATURAL AMINO ACIDS

该项目将提供有关结构的基本信息和 几种神经受体和离子通道(受体)的功能。 这些都是大脑和神经系统的基本分子.他们 是与许多疾病状态相关的关键结构，是 许多治疗方法的靶点。这项工作将使用一种新工具 最近在这些实验室中开发的-将非自然的 TH受体上特定位置的氨基酸及其蛋白的表达 在完好无损的细胞中。当与现代电生理方法相结合时， 这使得对结构和功能的研究具有前所未有的精度。 特别是，第一个目标系统将是烟碱型乙酰胆碱 受体。这是一个神经感受器的原型，代表了 一类广泛的重要结构。调查将揭示 配体(激动剂和拮抗剂)与 并产生特有的门控反应。这些研究 也将导致有关几何信息的发展 蛋白质的整体布局。当与现代计算机建模结合时 技术，这将产生可行的三维结构 受体的类别。第二个目标系统将是电压门控系统 钾通道及其相关结构。同样，这两个信息都是关于 将开发航道函数和精确的几何模型。

This project will provide fundamental information on the structure and function of several types of neuroreceptors and ion channels (receptors). These are the fundamental molecules of the brain an nervous system. They are athe crucial structures associated with many disease states and are the targets of many therapeutic approaches. The work will employ a new tool recently developed in these labs - the ability to incorporate unnatural amino acids at specific sites in th receptors and to express the proteins in intact cells. When coupled with modern electrophysiological methods, this allows study of structure and function with unprecedented precision. In particular, the first target system will be the nicotinic acetylcholine receptor. This is a prototype neuroreceptor and is representative of a broad class of important structures. The investigations will reveal the manner in which ligands (agonists and antagonists) interact with the receptor and produce the characteristic gating response. These studies will also lead to the development of geometrical information concerning the overall layout of the protein . When coupled with modern computer modeling techniques, this will produce viable, three-dimensional structures for this class of receptors. The second target system will be the voltage-gated potassium channels and related structures. Again, both information on channel function and precise geometrical models will be developed.