Dimensions and Polarity of Anesthetic Binding SItes

麻醉剂结合位点的尺寸和极性

• 批准号: 6620326
• 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
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-15 至 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6620326
• 关键词: GABA receptor; anesthetics; binding sites; cell morphology; cellular polarity; chemical binding; chemical models; computer simulation; gene mutation; glycine receptors; inhalation anesthesia; mathematical model; membrane channels; model design /development; molecular dynamics; molecular polarity; nicotinic receptors; protein structure; site directed mutagenesis

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 通过学习分子的设计和管理挥发性麻醉药 麻醉的机制。我们的短期目标是了解挥发性 跨膜的位点定向突变改变了麻醉效力 配体门控离子通道的域。我们的假设是内部的空腔 跨膜结构域为挥发性麻醉结合提供了一个共同的基序 GABA，甘氨酸，烟碱乙酰氨酸和 5-nt受体。我们建议特定的氨基酸残基定义 这些结合位点的维度和极性，从而确定 挥发性麻醉药的相对功效。该假设将在 两个具体的目标： 目标1。我们将检验以下假设 跨膜亚基内的空腔确定 GABA，甘氨酸和烟碱的超家族中的麻醉药 乙酰氨酸受体。两个关键氨基酸残基的突变 甘氨酸α1受体的跨膜段（S267和A288） 通过挥发性麻醉剂调节激动剂的增强。数量 这些残基是麻醉效力的最佳预测指标。我们将建造 这些亚基的跨膜结构域的分子模型并预测 可能定义这些推定腔的尺寸的其他残基。 AIM 2。我们将检验以下假设：腔的极性变化 在跨膜亚基内确定挥发性的相对效力 麻醉药。尽管氨基酸侧链的体积具有显性 效果，是麻醉剂对的独特体内和体外药理学 异构体证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进行研究的站点定向的突变 实验。 总之，我们具有两个跨膜alpha的初始计算模型 螺旋在合理化和预测的影响方面具有价值 定向突变。建立一个更完整的三维模型 麻醉结合位点将使我们能够定义那些分子特性 赋予挥发性麻醉药的不同药理学。