Cancer is a disease of mutation, and the most commonly mutated protein by far is the tumour suppressor p53. This protein, sometimes called the "Guardian of the Genome", does not only lead the major defence of the cell against cancer but also has a wide range of roles in the cell cycle, from fertility to senescence. It has a very complicated structure, comprised of two folded and three intrinsically disordered domains in each of its monomers that associate to form dimers and tetramers. It is a major hub protein and interacts with a host of other proteins involved in the cell cycle. We discovered that about 30% of oncogenic mutants of p53 are just temperatures sensitive and can, in theory, be rescued by small molecules.
Currently, we have two major projects. An MRC Programme Grant "Structural biology of the tumour suppressor p53 and its complexes" funds work to determine the structure of p53 and partner proteins, such as the Mdm2 and Mdm4, and their complexes. This work is a paradigm for solving the structures of partly disordered proteins, by combining a variety of structural methods.
An ERC Advanced Grant: "Tumour suppressor p53: structure, stability and novel anti-cancer drug development" funds work on finding the principles of stabilising p53 against denaturation and aggregation by small molecules for the rational design of drugs for rescue of mutants.
- Arbely, E., Natan, E., Brandt, T., Allen, M.D., Veprintsev, D.B., Robinson, C.V., Chin, J.W., Joerger, A.C. and Fersht, A.R. (2011)
Acetylation of lysine 120 of p53 endows DNA-binding specificity at effective physiological salt concentration.
Proc Natl Acad Sci U.S.A. 108: 8251-8256.
- Melero, R., Rajagopalan, S., Lázaro, M., Joerger, A.C., Lasso, G., Gil, D., Scheres, S., Carazo, J.M., Fersht, A.R. and Valle, M. (2011)
Electron microscopy studies on the quaternary structure of p53 reveal different binding modes for p53 tetramers in complex with DNA.
Proc Natl Acad Sci U.S.A. 108: 557-62.
- Basse, N., Kaar, J.L., Settanni, G., Joerger, A.C., Rutherford, T.J. and Fersht, A.R. (2010)
Towards the rational design of p53 stabilizing drugs: Probing the surface of the oncogenic Y220C Mutant
Chem Biol 17: 46-56.
- Andreas Joerger
- Miriana Petrovich
- Guozhen Wang
- Michal Bista