Further information
Dr Linda Ball, Leibniz Institute for Molecular Pharmacology, Berlin, Germany presents this lecture.
Abstract: My research focuses on understanding the determinants of specificity in protein-protein and protein-ligand interactions, with a view to better understanding and where possible, manipulating their function. Our research has focussed mainly on the protein-protein interactions mediated by different families of modular protein domains that are found again and again in a wide-range of host proteins, although often in different contexts, e.g. in different locations along the polypeptide chain, in different copy numbers and in varying combinations with other modular domains. Our work so far has mainly focused on the EVH1 domains and cofilins involved in regulation of the dynamic actin cytoskeleton, the RGS domains, crucial for regulation of G-protein signaling, the BRCT domains, important for tumour suppression and, most recently, the ‘Royal Family’ of chromodomains, essential for accurate control of transcription. The main goals of our work are:
– To identify high affinity peptide binding partners, derive consensus binding sequences and locate specificity-determining, and affinity enhancing residues, using peptide SPOTs arrays (Frank, J. Immunol. Methods, 267, 13-26, 2002).
– To compare interaction affinities of different binding partners and to elucidate whether they act as substrates or inhibitors, by performing in vitro functional assays (for example, mass spectrometry under reaction turnover conditions).
– To locate the structural determinants of ligand recognition by determining the high resolution structures of the domains, in various tandem combinations and in complex with peptides and/or full-length binding partners, using a combination of NMR spectroscopy and X-ray crystallography.To investigate the in-cell functions of identified interactions in yeast and mammalian cells in collaboration with cell biologists.
– To search for small molecule inhibitors of the above interactions using 1D 1H NMR screening (STD and/or WaterLOGSY) of small molecule compound libraries together with high throughput robotics (collaboration with FMP, Berlin). ‘Hits’ are validated independently using complementary biophysical methods. Such molecules will be useful as: (a) tools to dissect biochemical pathways; (b) molecular tags to monitor activity within the cell; (c) precursors for potential therapeutics.
As the above families of domains are commonly found in proteins regulating transcription, cell cycle, and apoptosis, an understanding the determinants of specific recognition in these protein domains could have an enormous impact on the future development of treatments for human cancers and related diseases.
For more information please contact Dr. Ernesto Cota, e.cota@imperial.ac.uk.