Modulating the ubiquitin ligase activity of MDM2

p53 tumour suppressor protein becomes activated in response to various genotoxic stresses and induces a variety signalling programmess to restore cellular homeostasis. Frequently, p53 is inactivated or mutated in cancers. Cancer cells that express wild type p53 often inactivate p53 by overexpressing ubiquitin ligases such as MDM2 and MDMX to target p53 for ubiquitination and degradation by the proteasome. Disruption of MDM2-p53 interaction by small molecules restores the wild-type p53 activity leading to cell cycle arrest and apoptosis in cancer cells. However, these small molecules often exhibited high on-target toxicity effects.

Recent work from the Huang lab showed that p53 activity could be activated with low toxicity through inactivation of MDM2's ubiquitin ligase activity. We have now identified molecules that bind the catalytic modules of MDM2 and MDMX. This project aims to characterise these molecules by elucidating their binding mechanisms through biophysical and structural analyses and to examine their effects on MDM2 and p53 in cells. The successful candidate will learn and apply techniques including molecular cloning, protein biochemistry, tissue culture assays, and structural characterisation by NMR, X-ray crystallography or Cryo-EM.

Keywords: Ubiquitin, MDM2, p53, biochemistry, structure