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Structural features of Eph Receptor-Ephrin Interaction

Eph 受体-Ephrin 相互作用的结构特征

基本信息

批准号：
8374767
负责人：
PETER KUHN
金额：
$ 25.63万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8374767
关键词：
Affinity Angiogenesis Inhibition Binding Biochemical Biological Cancerous Carcinogenesis Inhibition Cell-Cell Adhesion Cell-Matrix Junction Chemicals Cleaved cell Complement Complex Computer Analysis Crystallization Data Development Eph Family Receptors EphB2 Receptor EphB4 Receptor Ephrin-B2 Ephrins Exhibits Family Investigation Ligand Binding Ligand Binding Domain Ligands Malignant Neoplasms Molecular Molecular Conformation Molecular Weight Mutation Outcome Peptide Receptor Peptides Phosphotransferases Research Role Screening procedure Side Signal Transduction Specificity Structure Therapeutic Agents Tissues Translating Work X-Ray Crystallography angiogenesis anti-cancer therapeutic axonal guidance base cell motility design flexibility high throughput screening improved inhibitor/antagonist mutant overexpression protein function protein protein interaction receptor small molecule tool tumor growth tumorigenesis virtual

项目摘要

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.

Eph受体酪氨酸激酶家族和ephrin配体的信号级联已被研究