Objective The objective of this project is to increase our understanding of protein-ligand interactions by using a multidisciplinary approach that combines in a synergetic manner the structural-thermodynamic analysis of protein-ligand complexes and ligand-linked chimeras with a wide range of experimental techniques. We will apply this global approach to study the binding of peptidic ligands to SH3 domains and to analyse the binding effect propagation. SH3 domains receive and transmit information through specific interactions with other system components during propagation and amplification of cellular signalling and represent enticing targets for pharmacological intervention in a number of pathologies, such as, for instance, AIDS, cancer or osteoporosis. Understanding how information is transmitted through the structures of the domains will facilitate the development of new strategies for ligand design; i.e. strategies that optimise binding affinity, specificity and also modify the co-operative behaviour of the target protein in a predefined way. The structural parameterisation of the energetics of protein folding and protein-ligand binding resulted in the development by one of our groups of the design algorithms Perla and FOLDEF. Such a computational approach needs to be accompanied by extensive experimental work. X-ray crystallography, NMR and/or computer modelling will be used to obtain the structures of the protein-ligand complexes and ligand-bound chimeras. Calorimetry (ITC and DSC) will provide the experimental global thermodynamic magnitudes of the binding processes, which are necessary to test the validity of the calculations. NMR-detected hydrogen exchange and spin diffusion studies will be applied to acquire thermodynamic and dynamic information about local changes produced by binding or mutations. Using the above described approaches, it is intended: (i) To monitor the effects of small ligand changes on binding affinity and specificity, with the aim of designing improved ligands for SH3 domains. (ii) To define the cooperative pathways within the domains by using various types of the ligand-bound chimeras and single-point mutations either at the binding sites or at distant locations. (iii) To analyse how the protein-ligand interactions are transmitted through the protein structure and how ligands with different distribution of binding "hot spots" affect the structural cooperativity of the domains. (iv) To explore the possibility of designing the allosteric effectors, which could modulate the energetics of the poliproline ligand binding and signal transduction. (v) Finally, and more generally to obtain a series of parameters that would improve the existing design algorithms and allow the design of effective ligands for any protein-protein complex. Programme(s) IC-INTAS - International Association for the promotion of cooperation with scientists from the independent states of the former Soviet Union (INTAS), 1993- Topic(s) OPEN - OPEN Call Call for proposal Data not available Funding Scheme Data not available Coordinator EMBL EU contribution No data Address Meyerhofstraße 1 69012 Heidelberg Germany See on map Total cost No data Participants (3) Sort alphabetically Sort by EU Contribution Expand all Collapse all Russian Academy of Sciences Institute of Protein Research (IPR) Russia EU contribution No data Address Institutskaya 4 142290 Puschino See on map Total cost No data Russian Academy of Sciences Institute of Theoretical and Experimental Biophysics) Russia EU contribution No data Address Institutskaya 3 142290 Puschino See on map Total cost No data University of Granada, Faculty of Sciences Spain EU contribution No data Address Severo Ochoa 1 18071 Granada See on map Total cost No data
