Intrasteric regulation of MDM2

The oncoprotein murine double minute 2 (MDM2) binds to the tumour suppressor protein p53 and negatively regulates growth suppression by catalyzing the ubiquitination and degradation of p53. Antagonizing MDM2 is an ataxia telangiectasia mutated (ATM) kinase- and checkpoint kinase-2 (CHK2) -dependent DNA-damage-inducible pathway that phosphorylates p53, releases p53 from MDM2 control and stabilizes the p300-p53 transcription complex. A recent report has identified a pseudo-substrate domain in MDM2 that can act as a lid to cover the hydrophobic MDM2-pocket and suggests a novel mechanism for control of the stability of the MDM2-p53 protein complex in vivo.