Structural Study of the Insulin Receptor Tyrosine Kinase

描述(由申请人提供)：胰岛素的代谢和促进生长的作用是由胰岛素受体介导的，胰岛素受体是一种具有内在蛋白酪氨酸激酶活性的a2？2跨膜糖蛋白。胰岛素与受体的胞外区结合可诱导结构重排，从而促进胞浆区特定酪氨酸残基的自动磷酸化。酪氨酸磷酸化的作用是刺激受体的激活域的催化活性，并为下游信号蛋白创造募集位点。这项建议的总体目标是了解控制胰岛素信号的正负调节因子募集到胰岛素受体的结构/分子机制。 这项建议的具体目标是： 1.Grb14下调胰岛素受体的分子机制 2.PTP1B下调胰岛素受体的分子机制 3.IRS2募集到胰岛素受体并被其磷酸化的分子机制 将使用的主要实验技术是X射线结晶学、体外结合测量和基于细胞的功能分析。从这一建议中获得的结果将大大有助于我们理解胰岛素信号被传播和减弱的分子机制。 相关性：在发达国家，非胰岛素依赖型(II型)糖尿病的患病率正在以惊人的速度增长。通过在分子水平上了解胰岛素受体是如何调节的，我们希望促进设计小分子激动剂和抑制剂的努力，这些小分子激动剂和抑制剂可能被用于抗糖尿病治疗。

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.