STRUCTURAL STUDY OF THE INSULIN RECEPTOR TYROSINE KINASE

描述（改编自申请人摘要）：生理效应 胰岛素受体是胰岛素受体的一个成员， 具有内在酪氨酸激酶的细胞表面受体大家族 活动 这个家族还包括表皮生长的受体 因子（EGF）、成纤维细胞生长因子（FGF）和神经生长因子（NGF）， 还有其他的 配体结合后受体酪氨酸激酶的活化 是通过特定的酪氨酸残基的自磷酸化来实现的， 胞质结构域 对于胰岛素受体和许多其他受体 酪氨酸激酶，自磷酸化既刺激酪氨酸激酶 活性，并为下游信号蛋白提供结合位点， 识别特定序列背景下的磷酸酪氨酸。 具体 这项建议的目的是：1。 分子基础的确定 通过酪氨酸自磷酸化激活胰岛素受体。 2. 胰岛素受体底物结构决定簇的解析 的特异性 3. 分子表征的相互作用之间的 自磷酸化胰岛素受体和下游信号蛋白。 胰岛素受体酪氨酸激酶的X射线晶体学研究 不同的磷酸化状态，并与底物肽复合， 下游信号蛋白将是实现这些功能的主要手段。 目标。 从这项研究中获得的信息将提高我们对以下方面的认识： 胰岛素受体信号传导，并提供结构框架， 了解一些胰岛素受体的有害作用 导致非胰岛素依赖型糖尿病的突变。 结果 也适用于许多介导细胞增殖的生长因子受体， 生长和分化。 胰岛素的高分辨率结构 受体酪氨酸激酶应该证明在小分子设计中是有用的 针对导致癌症的酪氨酸激酶的抑制剂。

DESCRIPTION (Adapted from applicant's abstract): The physiological effects of the hormone insulin are mediated by the insulin receptor, a member of a large family of cell surface receptors with intrinsic tyrosine kinase activity. This family also includes the receptors for epidermal growth factor (EGF), fibroblast growth factor (FGF), and nerve growth factor (NGF), among others. Activation of receptor tyrosine kinases upon ligand binding is achieved through autophosphorylation of specific tyrosine residues in the cytoplasmic domain. For the insulin receptor and many other receptor tyrosine kinases, autophosphorylation both stimulates tyrosine kinase activity and provides binding sites for downstream signaling proteins that recognize phosphotyrosine in particular sequence contexts. The specific aims of this proposal are: 1. Determination of the molecular basis of insulin receptor activation via tyrosine autophosphorylation. 2. Elucidation of the structural determinants of insulin receptor substrate specificity. 3. Molecular characterization of the interactions between the autophosphorylated insulin receptor and downstream signaling proteins. X-ray crystallographic studies of the insulin receptor tyrosine kinase in different phosphorylation states and in complex with substrate peptides and downstream signaling proteins will be the primary means to accomplish these aims. The information gained from this study will enhance our knowledge of insulin receptor signaling and provide a structural framework for understanding the deleterious effects of a number of insulin receptor mutations that lead to non-insulin-dependent diabetes mellitus. The results will also be applicable to many growth factor receptors which mediate cell growth and differentiation. High-resolution structures of the insulin receptor tyrosine kinase should prove useful in the design of small molecule inhibitors targeted against tyrosine kinases that contribute to cancer.