Targeting the Conformational Transitions of MDM2 and MDMX. PART I: Insights into Dissimilarities and Similarities of p53 Recognition

MDM2 and MDMX are oncogenic homolog proteins that regulate the activity and stability of p53, a tumour suppressor protein involved in more than 50% of human cancers. While a number of pre-clinical and clinical studies have validated MDM2 as therapeutically important target for the development of anticancer drugs, it is only recently that MDMX has become an attractive target for the treatment of tumour cells expressing wild type p53. The availability of structural information of the N-terminal domain of MDM2 in complex with p53-derived peptides and inhibitors, and the very recent disclosure of the crystal structure of the N-terminal domain of MDMX bound to a p53 peptide, offer an unprecedented opportunity to get insight into the molecular basis of p53 recognition and the identification of discriminating features affecting the binding of the tumour suppressor protein at MDM2 and MDMX. In this first part of the study, we have explored the conformational transitions featuring the pathway leading from the apo-MDM2 and apo-MDMX states to the p53-bound MDM2 and p53-bound MDMX states, using spatial coarse graining simulations (SCGs). Compared to traditional molecular dynamic simulations, SCGs have as main advantages the low computational costs and the fastness to get a qualitative view of the conformational space of the protein. The major drawback of SCGs is the lack of information on the energy associated to the different conformational states of the protein. In this communication we will present the results of SCGS that have enabled us to identify a pool of diverse conformational states of the oncogenic proteins that affect the binding of p53, and the presence of conserved and non-conserved interactions along the conformational transition pathway that may be exploited to design selective and dual modulators of MDM2 and MDMX activity.