Grant: $239,118 - National Institutes of Health - Aug. 3, 2009
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Award Description: This proposal will delineate the structural features of a group o f 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 and 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 receptor. 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. Specific Aim 1. Describe the specificity determinants of the promiscuous EphA2, EphA4 and EphB2 receptors and compare them with the more selective EphB4 receptor. a) Structural characterization of the ligand binding domains of three different classes of Eph receptors to unveil the selectivity and promiscuity determinants of this group of protein-protein interactions. b) Biophysical characterization of wild-type and mutant Eph receptor ligand binding cavities (EphA2, EphA4, EphB2) with ligands and peptides to quantify the effects of Eph receptor mutations on ligand binding and specificity. Specific Aim 2. Characterize small molecular weight compounds found by screening against the EphB4 receptor ligand binding domains. Validation of hit compounds using both primary and secondary assays. Once compounds have been validated, we will optimize hit compounds using structure-based and computational design approaches to improve affinity and specificity for EphB4 ligand binding domain. This will be complemented with in vivo assays.
Project Description: As defined in Award Description field.
Infrastructure Description: NONE
Jobs Summary: The Recovery Act funds will enable us to retain one Research Associate who will perform the characterization of the Eph modulation by ligand petidic and small molecule compounds; and hire one Research Associate to conduct the structural biology experiments and guide and validate the systems developed for cloning, expression and purification of structure grade proteins of the Eph ligand binding domains and their ephrin ligands. (Total jobs reported: 1)
Project Status: Less Than 50% Completed
This award's data was last updated on Aug. 3, 2009. Help expand these official descriptions using the wiki below.