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MUTATIONAL ANALYSIS OF ANGIOTENSIN II RECEPTORS

血管紧张素 II 受体的突变分析

基本信息

批准号：
6389728
负责人：
DANIEL K YEE
金额：
$ 11.59万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-05-01 至 2002-11-30
项目状态：
已结题

项目摘要

DESCRIPTION: (Adapted from the Investigator's Abstract) It is well recognized that the central actions of angiotensin II (AngII) are importantly involved in the regulation of cardiovascular and body fluid homeostasis. Included amongst the actions of AngII in the brain are behavioral, endocrine, and physiological responses that result from the interaction of the peptide with cell surface receptors. There are two main families of AngII receptors, referred to as AT1 and AT2. Mutagenesis studies and computer modeling have primarily focused on the AT1 receptor, thereby leading to increasing understanding of the molecular mechanisms that define AT1 ligand binding and effector actions. In contrast, limited mutagenesis and no modeling studies have been performed on AT2 subtype. Because the two subtypes share only 34% homology, the extent that AT1 mutagenesis and modeling data are applicable to the AT2 receptor is currently unknown. Accordingly, in the present application, a series of AngII receptor mutants, in deletional mutations, AT1/AT2 chimeras, and point mutations, will be created and analyzed in order to identify the structural elements that define the ligand binding properties of AT2 receptors. Although these experiments focus primarily on the AT2 subtype, later comparison of similarities and differences with the AT1 receptor will provide insight into the ligand binding pocket of the entire AngII receptor family. In addition, because there is growing evidence that receptor dimerization may play an important role in modulating receptor function, the possible formation of AngII receptor dimers will also be studied. Specifically, this proposal will address: (i) identifying ion-pair interactions between AT2 receptor and AngII; (ii) the role of subtype-specific epitopes in the binding of AngII; (iii) the role of cysteine residues in the formation of disulfide bridges and as a source for the differing sensitivities of the two subtypes to the reducing agent dithiothreitol; (iv) identifying the structural elements that are responsible for AT2 subtype selective binding; and (v) investigating possible formation of AngII receptor dimers, either homologous or heterologous.

描述：（改编自研究者摘要）认识到血管紧张素II（AngII）的核心作用是重要参与心血管和体液的调节体内平衡 AngII在大脑中的作用包括行为，内分泌和生理反应，导致从肽与细胞表面受体的相互作用。主要有两血管紧张素Ⅱ受体家族，称为AT 1和AT 2。诱变研究和计算机建模主要集中在AT 1受体，从而加深对分子机制的理解，定义AT 1配体结合和效应子作用。相比之下，突变，并且没有对AT 2亚型进行建模研究。由于这两种亚型只有34%的同源性，AT 1 诱变和建模数据适用于AT 2受体，目前未知。因此，在本申请中，提供了一系列 AngII受体突变体，缺失突变，AT 1/AT 2嵌合体，和点突变，将被创建和分析，以确定结构定义AT 2受体的配体结合特性的元件。虽然这些实验主要集中在AT 2亚型，但后来与AT 1受体的相似性和差异性的比较将提供对整个AngII受体的配体结合口袋的深入了解家人此外，由于越来越多的证据表明，二聚化可能在调节受体功能中起重要作用，还将研究AngII受体二聚体的可能形成。具体而言，该提案将解决：（i）识别离子对 AT 2受体和AngII之间的相互作用;（ii）亚型特异性表位在AngII结合中的作用;（iii）半胱氨酸残基在二硫桥形成中的作用，两种亚型对还原剂的不同敏感性二硫苏糖醇;（iv）鉴定负责AT 2亚型选择性结合;和（v）研究可能形成AngII受体二聚体，同源或异源的