Molecular recognition and primary activation steps in BMP/GDF receptor complexes
Project management at the University of Würzburg:
The more than twenty known members of the BMP/GDF family play an important role as "bone morphogenetic proteins" or "growth and differentiation factors" in tissue-formation and -regeneration in the adult organism and they are involved in important steps of embryonal development throughout the animal kingdom. These factors cause the oligomerisation of two types of receptor chains in the plasma membrane and thus activating receptor serin kinases. For some representative members of the BMP/GDF-subfamilies with medical relevance the mechanisms of ligand receptor recognition are to be elucidated which affect the binding between the ligand and the receptor chains. For this purpose binding epitopes will be identified by mutation/interaction analyses and the quantitative contribution of single amino acid side chains to the kinetics and affinity of ligand receptor interaction determined. Additionally, crystal structure analysis of unbound receptors and in complex with the ligand will be performed to characterize the structure of the contact surface. We expect insights in the specificity of ligand receptor recognition, since the BMP and GDF ligands bind to different receptors and each receptor is able to bind more than one ligand. Furthermore, the relevance of high- and low affinity interactions for receptor oligomerisation and activation can be elucidated. The results will be used for the construction of suitable BMP/GDF variants (superagonists, selective agonists, antagonists) whose pharmacological properties will be tested in cell culture and animal models in terms of potential drug development.
Projekt period: from 01.2000 to 12.2002
DFG ( SFB 487 ) ,Granting date: 01.12.1999