Structural determinants of promiscuity and selectivity iin Ephrin_Eph binding.

Ephrin_Eph 结合中混杂性和选择性的结构决定因素。

基本信息

批准号：
7906742
负责人：
PETER KUHN
金额：
$ 29.91万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-03 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7906742
关键词：
Affinity Angiogenesis Inhibitors Area Binding Binding Sites Biochemical Biological Biological Assay Cancerous Carcinogenesis Inhibition Cell-Matrix Junction Complement Complex Consensus Sequence Crystallization Data Development Disease Eph Family Receptors EphB2 Receptor EphB4 Receptor Ephrins Exhibits Family Florida Glycosaminoglycans Grant Inhibitory Concentration 50 Investigation Ligand Binding Ligand Binding Domain Ligands Molecular Molecular Weight Mutation Outcome Peptides Phage Display Phosphotransferases Play Process Receptor Protein-Tyrosine Kinases Research Research Institute Resolution Role Screening procedure Signal Transduction Specificity Structure Therapeutic Therapeutic Agents Tissues Translating United States National Institutes of Health Validation Work angiogenesis anti-cancer therapeutic axonal guidance base cell growth cell motility design flexibility high throughput screening improved in vivo member mutant overexpression protein function protein protein interaction receptor repository small molecule therapeutic development tool tumorigenesis virtual

项目摘要

This proposal will delineate the structural features of a group of Eph receptors (EphB2, EphA2, and EphA4) in their apo forms as well as in complex with their cognate ligands and peptides. These receptors are members of the largest receptor tyrosine kinase family identified to date, and have proven implications in both angiogenesis an tumorigenesis. The structure-function results of this proposal will provide a comprehensive description of the receptor/ligand interfaces across the family, including highly promiscuous receptors (EphB2, EphA4) and highly specific receptors (EphB4, EphA2). The combination of results from the structural analysis of the Eph receptor/ligand complexes and quantitative biophysical assays of Eph receptor-ligand binding will provide a set of structural determinants that can be used to optimize compound development for a specific Eph receptor. We have performed a high throughput screen with a mutant EphB4 receptor that was identified to show reduced affinity for the target ligand, the TNYL-RAW peptide. Nine compounds were identified form a small molecule compound repository at the NIH that selectively bind the EphB4 ligand binding domain. We will characterize all available compounds and compounds and compounds from similarity searches in cellular and structural assays. Given the important roles that EphB4, EphB2, EphA2 and EphA4 play in several disease areas including tumorigenesis, molecules specific for these receptors would form validated starting points for therapeutic compound development targeting processes involving protein-protein interactions such as angiogenesis and cell growth. Our studies will provide both the structural determinants and biophysical information that characterize the specific binding of these molecules to their target Eph receptors and will form a strong basis for further therapeutic development.

该提案将描述一组 Eph 受体（EphB2、EphA2、和 EphA4) 的 apo 形式以及与其同源配体和肽的复合物。这些受体是迄今为止发现的最大受体酪氨酸激酶家族的成员，并且已证明对血管生成和肿瘤发生都有影响。结构-功能结果该提案将提供跨受体/配体界面的全面描述家族，包括高度混杂的受体（EphB2、EphA4）和高度特异性的受体（EphB4，EphA2）。 Eph结构分析结果的组合受体/配体复合物和 Eph 受体-配体结合的定量生物物理测定将提供一组可用于优化化合物开发的结构决定因素对于特定的 Eph 受体。我们对突变型 EphB4 受体进行了高通量筛选，该受体被鉴定为显示对目标配体 TNYL-RAW 肽的亲和力降低。九种化合物是从 NIH 的小分子化合物库中鉴定出选择性结合 EphB4 配体结合域。我们将表征所有可用的化合物和化合物通过细胞和结构分析中的相似性搜索获得化合物。鉴于 EphB4、EphB2、EphA2 和 EphA4 在多个疾病领域发挥的重要作用包括肿瘤发生，这些受体特异的分子将形成经过验证的起始治疗性化合物开发的要点涉及蛋白质-蛋白质的靶向过程相互作用，例如血管生成和细胞生长。我们的研究将提供结构表征这些特定结合的决定因素和生物物理信息分子与其目标 Eph 受体结合，将为进一步治疗奠定坚实的基础发展。