Dimensions and Polarity of Anesthetic Binding SItes

麻醉剂结合位点的尺寸和极性

基本信息

批准号：
6693066
负责人：
JAMES Robert TRUDELL
金额：
$ 9.89万
依托单位：
STANFORD 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：
2002-01-15 至 2005-12-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Our long-term goal is to improve the design and administration of volatile anesthetics by learning the molecular mechanisms of anesthesia. Our short-term goal is to understand how volatile anesthetic potency is altered by site-directed mutations in the transmembrane domains of ligand-gated ion channels. Our hypothesis is that cavities within transmembrane domains provide a common motif for volatile anesthetic binding sites within the superfamily of GABA, glycine, nicotinic acetyicholine, and 5-NT receptors. We suggest that specific amino acid residues define the dimensions and polarity of these binding sites and thereby determine the relative efficacy of volatile anesthetics. This hypothesis will be tested in two Specific Aims: Aim 1. We will test the hypothesis that variations in the dimensions of cavities within transmembrane subunits determine the relative potency of anesthetics within the superfamily of GABA, glycine, and nicotinic acetyicholine receptors. Mutation of two critical amino acid residues in transmembrane segments of the glycine alpha 1 receptor (S267 and A288) modulates the potentiation of agonists by volatile anesthetics. The volume of these residues is the best predictor of anesthetic potency. We will build molecular models of the transmembrane domains of these subunits and predict additional residues that may define the dimensions of these putative cavities. Aim 2. We will test the hypothesis that variations in the polarity of cavities within transmembrane subunits determine the relative potency of volatile anesthetics. Although the volume of amino acid side-chains has a dominant effect, the distinct in vivo and in vitro pharmacology of pairs of anesthetic isomers demonstrate that the polarity and shape of binding sites is important. We will use molecular modeling to rationalize existing data and predict new site-directed mutations for study by our collaborators in an iterative series of experiments. In summary, our initial computational models with two transmembrane alpha helices have been of value in rationalizing and predicting the effect of site-directed mutations. Building a more complete 3-dimensional model of an anesthetic binding site will allow us to define those molecular properties that confer distinct pharmacologies on volatile anesthetics.

描述（由申请人提供）：我们的长期目标是改善通过学习分子原理来设计和管理挥发性麻醉剂麻醉机制。我们的短期目标是了解波动性如何跨膜定点突变改变麻醉效力配体门控离子通道的域。我们的假设是，内部的空洞跨膜结构域为挥发性麻醉剂结合提供了共同基序 GABA、甘氨酸、烟碱乙酰胆碱等超家族中的位点 5-NT 受体。我们建议特定的氨基酸残基定义这些结合位点的尺寸和极性，从而确定挥发性麻醉剂的相对功效。该假设将在两个具体目标：目标 1. 我们将检验以下假设：跨膜亚基内的空腔决定了跨膜亚基的相对效力 GABA、甘氨酸和烟碱超家族中的麻醉剂乙酰胆碱受体。两个关键氨基酸残基的突变甘氨酸 α 1 受体的跨膜片段（S267 和 A288）通过挥发性麻醉剂调节激动剂的增强作用。体积为这些残留物是麻醉效力的最佳预测指标。我们将建设这些亚基跨膜域的分子模型并预测可以定义这些假定空腔尺寸的附加残基。目标 2. 我们将检验以下假设：空腔极性的变化跨膜亚基内确定挥发性物质的相对效力麻醉剂。虽然氨基酸侧链的体积占主导地位作用、不同的体内和体外药理学对麻醉剂异构体表明结合位点的极性和形状很重要。我们将使用分子建模来合理化现有数据并预测新的数据我们的合作者在迭代系列中研究的定点突变实验。总之，我们最初的计算模型具有两个跨膜 α 螺旋在合理化和预测效应方面具有重要价值定点突变。建立更完整的 3 维模型麻醉剂结合位点将使我们能够定义那些分子特性赋予挥发性麻醉剂独特的药理学作用。