Dimensions and Polarity of Anesthetic Binding SItes

简介(申请人提供)：我们的长远目标是改善 通过学习分子设计和给药挥发性麻醉药 麻醉机制。我们的短期目标是了解波动性 跨膜上的定点突变改变了麻醉剂的效力 配基门控离子通道的结构域。我们的假设是里面的空洞 跨膜结构域为挥发性麻醉剂结合提供了一个共同的基序 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 这些结合部位的尺寸和极性，从而决定了 挥发性麻醉药的相对疗效。这一假设将在#年进行检验。 两个具体目标： 目标1。我们将检验这样一个假设，即维度的变化 跨膜亚单位内的空洞决定了相对效力 GABA、甘氨酸和烟酸超家族中的麻醉药 乙酰胆碱受体。猪瘟病毒两个关键氨基酸残基的突变 甘氨酸α1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。的音量 这些残留物是麻醉剂效力的最佳预测指标。我们将建造 这些亚基跨膜结构域的分子模型和预测 可能定义这些假定空洞的尺寸的附加残基。 目标2.我们将检验这样一种假设，即空洞极性的变化 在跨膜亚基内决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优势 两种麻醉剂的药效、体内外药理研究进展 异构体表明，结合部位的极性和形状很重要。 我们将使用分子建模来理顺现有数据并预测新的 用于我们的合作者在迭代序列中研究的定点突变 实验的结果。 总而言之，我们最初的计算模型有两个跨膜α 螺旋在合理化和预测的效果方面有价值 定点突变。构建更完整的三维模型 麻醉剂结合部位将允许我们定义这些分子特性 赋予挥发性麻醉剂不同的药理作用。

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.