Nutlin mediates MDM2-p53 binding interactions via novel additional site: a new window on drug discovery?

One of the drugs that has been shown to reduce MDM2-p53 binding affinity in in-vitro studies is a nutley inhibitor compound (nutlin). X-ray crystallography revealed that nutlin binds to MDM2 at the same site where p53’s transactivation domain binds to, suggesting that nutlin is a competitive inhibitor. However, X-ray crystallography and hydrogen-deutirium exchange studies have also revealed the presence of a secondary binding site! In this study, we attempt to characterize the secondary site to elucidate its role in mediating MDM2-p53’s binding.