Structural Study of the Insulin Receptor Tyrosine Kinase

性状（由申请方提供）：胰岛素的代谢和生长刺激作用由胰岛素受体介导，胰岛素受体是一种具有内在蛋白酪氨酸激酶活性的α 2 <$2跨膜糖蛋白。胰岛素与受体的胞外结构域结合诱导结构重排，促进胞质结构域中特定酪氨酸残基的自磷酸化。酪氨酸磷酸化用于刺激受体的激酶结构域的催化活性，并为下游信号传导蛋白产生募集位点。本提案的总体目标是了解胰岛素信号传导的正性和负性调节因子向胰岛素受体募集的结构/分子机制。 该提案的具体目标是： 1. Grb 14下调胰岛素受体的分子机制 2. PTP 1B下调胰岛素受体的分子机制 3.胰岛素受体募集和磷酸化IRS 2的分子机制 要使用的主要实验技术是X射线晶体学，体外结合测量，和基于细胞的功能测定。从这个建议中获得的结果应该有助于我们理解胰岛素信号传播和衰减的分子机制。 相关性：发达国家非胰岛素依赖型（II型）糖尿病的发病率正在以惊人的速度增加。通过在分子水平上了解胰岛素受体如何调节，我们希望促进设计可能用作抗糖尿病治疗药物的小分子激动剂和抑制剂的努力。

DESCRIPTION (provided by applicant): The metabolic and growth-stimulatory effects of insulin are mediated by the insulin receptor, an a2¿2 transmembrane glycoprotein with intrinsic protein tyrosine kinase activity. Insulin binding to the extracellular domains of the receptor induces a structural rearrangement that facilitates autophosphorylation of specific tyrosine residues in the cytoplasmic domains. Tyrosine phosphorylation serves to stimulate the catalytic activity of the kinase domain of the receptor and to create recruitment sites for downstream signaling proteins. The overall goal of this proposal is to understand the structural/molecular mechanisms governing recruitment to the insulin receptor of positive and negative regulators of insulin signaling. The Specific Aims of this proposal are: 1. Molecular mechanisms governing downregulation of the insulin receptor by Grb14 2. Molecular mechanisms underlying downregulation of the insulin receptor by PTP1B 3. Molecular mechanisms governing IRS2 recruitment to and phosphorylation by the insulin receptor The main experimental techniques to be used are x-ray crystallography, in vitro binding measurements, and cell-based functional assays. The results obtained from this proposal should contribute significantly to our understanding of the molecular mechanisms by which insulin signaling is propagated and attenuated. Relevance: The prevalence of non-insulin-dependent (type II) diabetes is increasing at an alarming rate in developed countries. By understanding at the molecular level how the insulin receptor is regulated, we hope to facilitate efforts to design small-molecule agonists and inhibitors that could potentially be used as anti-diabetic therapeutics.