LIGAND BINDING SITES OF THE ACETYLCHOLINE RECEPTOR

乙酰胆碱受体的配体结合位点

基本信息

批准号：
6393797
负责人：
STEEN E PEDERSEN
金额：
$ 31.59万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-06-01 至 2003-06-30
项目状态：
已结题

项目摘要

The long-term aim of this research is to understand the regulation of ligand-gated ion channels by the binding of neurotransmitters. The particular goal of this application is to understand the importance of charge-charge interactions in the regulation of the nicotinic acetylcholine receptor by the binding of acetylcholine. Specifically, the structure activity relationship of d-tubocurarine to the nicotinic acetylcholine receptor will be examined by analyzing the binding of d-tubocurarine analogs to native and mutated acetylcholine receptors. The role of electrostatic attraction in binding will be examined to determine whether charge- charge attraction governs the rapid rate of acetylcholine binding and contributes to the stabilization of the agonist cation. The channel movements associated with the conformational transition of the acetylcholine receptor will be measured by mutagenesis of residues near the narrow pore of the channel, and by direct measurements of electrostatic potential using fluorescence lifetime spectroscopic methods. The experiments will define functionally relevant components of the receptor structure that contribute to ligand binding, to ion channel structure, and to function. This will improve our understanding of synaptic transmission, a process that underlies the complex phenomena of learning, memory and thought. The skeletal muscle nicotinic acetylcholine receptor (and particularly the extracellular domain) is the target of autoimmune antibodies in the disease Myasthenia Gravis. The neuronal homologues of this protein are involved in nicotine addiction and possibly in Alzheimer's disease. A better understanding of the structure of this protein and especially the acetylcholine binding sites will be important for a full understanding of these ailments and for developing treatments. A fundamental understanding of the binding site stricture will improve rational drug design for this protein while the methodology proposed here may constitute a new paradigm for rational drug design for receptor targets in general.

这项研究的长期目的是通过神经递质的结合来了解配体门控离子通道的调节。该应用的特殊目标是了解通过乙酰胆碱的结合，电荷荷兰相互作用在调节烟碱乙酰胆碱受体中的重要性。具体而言，将通过分析D-微核心类似物与天然和突变的乙酰胆碱受体的结合来检查D-微量洲际素与烟碱乙酰胆碱受体的结构活性关系。将检查静电吸引力在结合中的作用，以确定电荷吸引力是否控制乙酰胆碱结合的快速速率，并有助于激动剂阳离子的稳定。与乙酰胆碱受体的构象转变相关的通道运动将通过在通道狭窄孔附近的残基以及使用荧光寿命光谱方法直接测量静电电位的诱变来测量。该实验将定义受体结构的功能相关成分，这些组件有助于配体结合，与离子通道结构和功能。这将提高我们对突触传播的理解，这一过程是学习，记忆和思想的复杂现象的基础。骨骼肌烟碱乙酰胆碱受体（尤其是细胞外结构域）是该病肌无力肌无力的肌无力的靶标。该蛋白质的神经元同源物与尼古丁成瘾有关，可能与阿尔茨海默氏病有关。更好地理解该蛋白质的结构，尤其是乙酰胆碱结合位点，对于对这些疾病的充分理解和开发治疗非常重要。对结合位点狭窄的基本理解将改善该蛋白质的合理药物设计，而此处提出的方法可能构成了通常用于受体靶标的合理药物设计的新范式。