Dimensions and Polarity of Anesthetic Binding SItes

麻醉剂结合位点的尺寸和极性

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/6693066
• 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）：我们的长期目标是提高 通过了解分子结构设计和给药挥发性麻醉剂 麻醉机制。我们的短期目标是了解 麻醉效力通过跨膜中的定点突变而改变 配体门控离子通道域。我们的假设是 跨膜结构域提供了挥发性麻醉剂结合的共同基序 GABA、甘氨酸、烟碱乙酰胆碱和 5-NT受体。我们认为，特定的氨基酸残基定义了 这些结合位点的尺寸和极性，从而决定 挥发性麻醉药的相对有效性。这一假设将在 两个具体目标： 目标1.我们将测试的假设，在尺寸的变化， 跨膜亚基内的空腔决定了 GABA、甘氨酸和烟碱超家族内的麻醉剂 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。的体积 这些残留物是麻醉剂效力的最佳预测物。我们将建立 这些亚基的跨膜结构域的分子模型，并预测 可以限定这些推定空腔的尺寸的额外残基。 目标2.我们将检验一个假设，即空穴极性的变化 在跨膜亚基内， 麻醉剂虽然氨基酸侧链的体积占主导地位， 效果，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是重要的。 我们将使用分子建模来合理化现有的数据，并预测新的 我们的合作者在一个迭代系列中研究定点突变 的实验。 总之，我们的初始计算模型具有两个跨膜α 螺旋在合理化和预测 定点突变建立一个更完整的三维模型， 麻醉剂结合位点将允许我们定义那些分子特性， 赋予挥发性麻醉剂不同的药理学。

项目成果

Molecular targets and mechanisms for ethanol action in glycine receptors.

• DOI: 10.1016/j.pharmthera.2010.03.003
• 发表时间: 2010-07
• 期刊: PHARMACOLOGY & THERAPEUTICS
• 影响因子: 13.5
• 作者: Perkins, Daya I.;Trudell, James R.;Crawford, Daniel K.;Alkana, Ronald L.;Davies, Daryl L.
• 通讯作者: Davies, Daryl L.