Structural features of Eph Receptor-Ephrin Interaction

Eph受体酪氨酸激酶家族和Ephin配体的信号级联已被 与血管生成和肿瘤形成的病理形式有关。虽然最初的投资集中在 关于这种蛋白质-蛋白质相互作用在轴突引导、细胞附着和运动中的作用，现在有 这一相互作用在多种癌症中过度表达和失调的重要证据 纸巾。这一提议的关键研究假设是，有限的结构性决定因素集是 对Eph受体家族表现出的配基识别的混杂和选择性负责，以及 这些结构决定因素可以用来作为这种相互作用的小分子调节剂。这个 拟议的研究将导致对绑定模式的演示描述和特征 在这个受体-配体相互作用的大家族中。这一结果将被翻译成一项发现 开发利用这些结构决定因素的小分子化合物的方法。 目的1：通过以下方法评估Eph受体-配体结合中特异性与杂交性的结构决定因素 使用X射线结晶学。 目的2：制定策略稳定Ephin结合裂隙中灵活的Eph受体J-K环以促进 受体结晶在与小分子化合物的络合物中。 目的3：鉴定和改进高通量鉴定的小分子化合物 EphB2和EphB4受体配体结合抑制剂的筛选和虚拟配体筛选。

The signaling cascades of the Eph receptor tyrosine kinase family and the ephrin ligands have been implicated in pathological forms of angiogenesis and tumorigenesis. While initial invesfigations have focused on the role of this protein-protein interaction in axonal guidance, cell attachment and motility, there is now signiflcant evidence forthe overexpression and dysregulation of this interaction in numerous cancerous tissues. The key research hypothesis of this proposal is that a limited set of structural determinants are responsible for the promiscuity and selectivity of ligand recognifion exhibited by the Eph receptor family, and that these structural determinants can be exploited for small molecule modulators of this interaction. The proposed research will result in a demonstrated descripfion and characterizafion of the mode of binding across this large family of receptor-ligand interactions. The outcome will be translated in a discovery approach to the development of small molecule compounds that exploit these structural determinants. Aim 1: Evaluate structural determinants of specificity versus promiscuity in Eph receptor-ligand binding by using X-ray crystallography. Aim 2: Develop strategies to stabilize the flexible Eph receptor J-K loop in the ephrin-binding cleft to facilitate receptor crystallization in complex with small molecular weight chemical compounds. Aim 3: Characterize and improve small molecular weight chemical compounds identified in high throughput screens and virtual ligand screens for inhibitors of EphB2 and EphB4 receptor ligand binding.