STRUCTURE & FUNCTION OF BINDING SITE OF INSULIN RECEPTOR

这项建议的目标是确定胰岛素的区域 胰岛素结合的受体分子及其在胰岛素中的作用 确定配基的特异性和启动信号转导。 胰岛素抵抗通常与糖耐量异常有关。 人类，特别是患有非胰岛素依赖型糖尿病的人。 最近，胰岛素受体的遗传缺陷被证明是 对极端胰岛素抵抗的某些症状负责。因此， 对胰岛素结合位点结构和功能的认识 胰岛素受体应能进一步深入了解糖尿病的发病机制 胰岛素抵抗。此外，从这项研究中获得的知识可以 导致具有更强特异性的修饰胰岛素的开发 代谢反应而不是有丝分裂反应，具有更大的效力。 这个实验室以前的研究已经确定了一个重要的作用 胰岛素受体中的苯丙氨酸89与胰岛素结合。这将是 作为确定更广泛区域的起点 定点突变胰岛素结合受体的研究 利用胰岛素结构域构建嵌合分子 和胰岛素样生长因子I受体。 拟议研究的具体目标是： 1.确定与胰岛素结合有关的受体区域 2.利用定点突变来确定个体的角色 胰岛素结合中的氨基酸 3.评价异源四聚体受体结构在 高亲和力配体结合 4.确定胰岛素中个别氨基酸的作用 启动对胰岛素的生物反应的结合区 5.确定胰岛素结合部位在抑制中的作用 受体自磷酸化与生物活性

The objective of this proposal is to identify the regions of the insulin receptor molecule to which insulin binds and to identify their role in determining ligand specificity and in initiating signal transduction. Insulin resistance is commonly associated with glucose intolerance in humans, particularly with non-insulin dependent diabetes mellitus. Recently genetic defects of the insulin receptor have been shown to be responsible for certain syndromes of extreme insulin resistance. Thus understanding of the structure and function of the insulin binding site of the insulin receptor should provide further insights into the pathology of insulin resistance. Moreover knowledge obtained from this study could lead to the development of modified insulins with greater specificity for metabolic rather than mitogenic responses and with greater potency. Previous studied in this laboratory have identified an important role for phenylalanine 89 of the insulin receptor in insulin binding. This will serve as a starting point for the identification of more extensive regions of the receptor involved in insulin binding by site directed mutagenesis and the construction of chimeric molecules utilizing domains of the insulin and insulin-like Growth Factor I receptors. The specific aims of the proposed research are: 1. To identify regions of the receptor involved in insulin binding 2. To utilize site directed mutagenesis to define the roles of individual amino acids in insulin binding 3. To evaluate the role of the hetero-tetrameric receptor structure in high affinity ligand binding 4. To determine the roles of individual amino acids within the insulin binding region in initiating biological responses to insulin 5. To determine the role of the insulin binding site in suppressing receptor autophosphorylation and biological activity