STRUCTURE & FUNCTION OF BINDING SITE OF INSULIN RECEPTOR

该提案的目的是确定胰岛素的区域， 胰岛素受体分子结合，并确定其作用， 确定配体特异性和启动信号转导。 胰岛素抵抗通常与葡萄糖耐受不良有关， 人，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已被证明是 导致某些极端胰岛素抵抗综合症 因此 了解胰岛素结合位点的结构和功能， 胰岛素受体应该提供进一步的了解病理学 胰岛素抵抗 此外，从这项研究中获得的知识可以 导致开发具有更大特异性的修饰胰岛素， 代谢反应而不是促有丝分裂反应，并且具有更大的效力。 该实验室以前的研究已经确定了 在胰岛素结合中，胰岛素受体的苯丙氨酸89。 这将 作为确定更广泛区域的起点 通过定点突变， 以及利用胰岛素的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作用 胰岛素结合氨基酸 3. 评估异源四聚体受体结构在 高亲和力配体结合 4. 确定胰岛素中单个氨基酸的作用 启动对胰岛素的生物反应的结合区 5. 为了确定胰岛素结合位点在抑制 受体自身磷酸化与生物活性

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