Mechanism of Competition between Nutlin3 and p53 for Binding with Mdm2

The tumour suppressor p53 is a transcription factor that regulates multiple biological functions including metabolism, DNA repair, cell cycle arrest, apoptosis and senescence. About half of human cancers show a normal TP53 gene and aberrant overexpression of Mdm2. This fact promotes a promising cancer therapeutic strategy by inhibiting the interactions between p53 and Mdm2. Various inhibitors have been designed to achieve this novel approach for cancer therapy. However, the detailed competition mechanism between these inhibitors and the p53 molecule in their binding process to Mdm2 is still unclear. We investigate this competition mechanism between Nutlin3 and p53 using molecular dynamics simulations. It is found that Nutlin3 binds faster than the p53 molecule to Mdm2 to prevent p53 binding to Mdm2 when Nutlin3 and p53 have equal distance from Mdm2. Nutlin3 can also bind to the p53-Mdm2 complex to disturb and weaken the interactions between p53 and Mdm2. Consequently, p53 cannot bind to Mdm2 and its tumour suppression function is reactivated. These results provide the detailed competition mechanism between Nutlin3 and p53 in their binding to Mdm2. Because the binding site of most other inhibitors to Mdm2 is the same as Nutlin3, therefore this competition mechanism can extend to most inhibitors which target the p53-Mdm2 interaction.