.G protein-coupled receptors (GPCRs) are membrane proteins responsible for transmitting the signal carried by a variety of extracellular stimuli, such as hormones or signalling peptides, across the cellular membrane. These proteins are very important in cell physiology, and their malfunction is linked to many diseases. Therefore, they are targets for numerous therapeutic molecules. Some GPCRs can recognise several ligands, with diverse physiological and pharmacological outputs. One of the most important questions is to understand how ligands can induce distinct conformations in GPCRs and activate different downstream signalling pathways. The aim of the proposed research is to identify the number of distinct conformational states, to structurally characterise ligand-induced conformational changes in GPCRs and to engineer conformationally stabilised variants for subsequent biophysical, NMR and crystallographic studies. To achieve this goal I will use a combination of protein engineering and rigorous biophysical analysis. I have successfully used this multidisciplinary approach to study the equally challenging tumour suppressor p53 and its recognition of DNA.
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"Conservation of DNA-binding specificity and oligomerisation properties within the p53 family."
Brandt T, Petrovich M, Joerger AC and Veprintsev DB.
BMC Genomics 2009 10:628.
"Algorithm for prediction of tumour suppressor p53 affinity for binding sites in DNA."
Veprintsev DB and Fersht AR.
Nucleic Acids Research 2008 36:1589-1598.
"Core domain interactions in full-length p53 in solution."
Veprintsev DB, Freund SM, Andreeva A, Rutledge SE, Tidow H, Canadillas JM, Blair CM and Fersht AR.
Proceedings of the National Academy of Sciences of the United States of America 2006 103:2115-2119.