Structural biology of the tumour suppressor p53 and its complexes

The body has defence mechanisms against cancer that involve a protein called p53. This protein also has important roles in many other biological processes, ranging from fertility to ageing. When p53 receives signals that a cell is becoming cancerous, the protein sets into action a train of events that eventually lead to the cancer cell being destroyed. For cancer cells to survive, the activities of p53 have to be eliminated. About half of human cancers have their p53 being disabled by a mutation, most likely caused by environmental damage or radiation. In many cancers, there are raised levels of proteins that inactivate or destroy p53. Our studies examine the shapes of p53 and the other proteins and how they all fit together. These studies will provide fundamental information for designing new anti-cancer drugs that will protect p53.

Intrinsically disordered domains are now known to be crucial, functional components of many proteins, especially those involved in cell signalling and regulation of the cell cycle. The presence of disordered regions prevents those proteins being crystallised for structural studies, and so solution of their structures is a major challenge, requiring techniques other than x-ray crystallography. The tumour suppressor p53 is an archetypical example of such a protein, as are its negative regulators MDM2 and MDMX. p53 is inactivated directly by mutation in ~50% of human cancers and its apoptopic pathways impaired in the remainder, often by raised levels of MDM2 and MDMX. We have recently solved the structure of p53 in solution using a combination of state-of-the-art NMR spectroscopy, small-angle-x-ray scattering, other biophysical and structural methods, protein engineering and computation. We now wish to do the same for MDMX and MDM2, and their complexes with p53. We wish to reconstruct the structure of p53 and its complexes in solution in order to understand the relationship between p53s structure and activity and how it is regulated by post-translational modification and interaction with other partner proteins. These studies will provide fundamental information on the control of the cell cycle and aid in the development of novel anti-cancer drugs. We have the necessary preliminary data to ensure that these studies should be successful.