Paul H. Kussie, Svetlana Gorina, Vincent Marechal, Brian Elenbaas, Jacque Moreau, Arnold J. Levine, Nikola P. Pavletich ^*

The MDM2 oncoprotein is a cellular inhibitor of the p53 tumor suppressor in that it can bind the transactivation domain of p53 and downregulate its ability to activate transcription. In certain cancers, MDM2 amplification is a common event and contributes to the inactivation of p53. The crystal structure of the 109-residue amino-terminal domain of MDM2 bound to a 15-residue transactivation domain peptide of p53 revealed that MDM2 has a deep hydrophobic cleft on which the p53 peptide binds as an amphipathic  helix. The interface relies on the steric complementarity between the MDM2 cleft and the hydrophobic face of the p53  helix and, in particular, on a triad of p53 amino acids--Phe¹⁹, Trp²³, and Leu²⁶--which insert deep into the MDM2 cleft. These same p53 residues are also involved in transactivation, supporting the hypothesis that MDM2 inactivates p53 by concealing its transactivation domain. The structure also suggests that the amphipathic  helix may be a common structural motif in the binding of a diverse family of transactivation factors to the TATA-binding protein-associated factors.

P. H. Kussie, S. Gorina, and N. P. Pavletich are with the Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
V. Marechal is with the Cervice de Microbiologie, Hopital Rothschild, F-75571, Paris 12, France.
B. Elenbaas and A. J. Levine are in the Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
J. Moreau is at the Institut Jacque Monad, Equipe d'Embryologie, 75251, Paris, France.
^*   To whom correspondence should be addressed. E-mail: nikola{at}xray2.mskcc.org