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Science 8 November 1996:
Vol. 274. no. 5289, pp. 948 - 953
DOI: 10.1126/science.274.5289.948
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Research Articles

Structure of the MDM2 Oncoprotein Bound to the p53 Tumor Suppressor Transactivation Domain

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 alpha  helix. The interface relies on the steric complementarity between the MDM2 cleft and the hydrophobic face of the p53 alpha  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 alpha  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

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   Abstract »    Full Text »    PDF »
Effect of Phosphorylation on the Structure and Fold of Transactivation Domain of p53.
S. Kar, K. Sakaguchi, Y. Shimohigashi, S. Samaddar, R. Banerjee, G. Basu, V. Swaminathan, T. K. Kundu, and S. Roy (2002)
J. Biol. Chem. 277, 15579-15585
   Abstract »    Full Text »    PDF »
Mutation of Mouse p53 Ser23 and the Response to DNA Damage.
Z. Wu, J. Earle, S.'i. Saito, C. W. Anderson, E. Appella, and Y. Xu (2002)
Mol. Cell. Biol. 22, 2441-2449
   Abstract »    Full Text »    PDF »
ATM Mediates Phosphorylation at Multiple p53 Sites, Including Ser46, in Response to Ionizing Radiation.
S.'i. Saito, A. A. Goodarzi, Y. Higashimoto, Y. Noda, S. P. Lees-Miller, E. Appella, and C. W. Anderson (2002)
J. Biol. Chem. 277, 12491-12494
   Abstract »    Full Text »    PDF »
Small-molecule antagonists of Myc/Max dimerization inhibit Myc-induced transformation of chicken embryo fibroblasts.
T. Berg, S. B. Cohen, J. Desharnais, C. Sonderegger, D. J. Maslyar, J. Goldberg, D. L. Boger, and P. K. Vogt (2002)
PNAS 99, 3830-3835
   Abstract »    Full Text »    PDF »
A Transcriptionally Inactive E2F-1 Targets the MDM Family of Proteins for Proteolytic Degradation.
G. D. Strachan, R. Rallapalli, B. Pucci, T. P. Lafond, and D. J. Hall (2001)
J. Biol. Chem. 276, 45677-45685
   Abstract »    Full Text »    PDF »
The N-terminal Regions of Estrogen Receptor alpha and beta Are Unstructured in Vitro and Show Different TBP Binding Properties.
A. Warnmark, A. Wikstrom, A. P. H. Wright, J.-A. Gustafsson, and T. Hard (2001)
J. Biol. Chem. 276, 45939-45944
   Abstract »    Full Text »    PDF »
Identification of Acidic and Aromatic Residues in the Zta Activation Domain Essential for Epstein-Barr Virus Reactivation.
Z. Deng, C.-J. Chen, D. Zerby, H.-J. Delecluse, and P. M. Lieberman (2001)
J. Virol. 75, 10334-10347
   Abstract »    Full Text »    PDF »
Osmotic Shock Induces G1 Arrest through p53 Phosphorylation at Ser33 by Activated p38MAPK without Phosphorylation at Ser15 and Ser20.
H. Kishi, K. Nakagawa, M. Matsumoto, M. Suga, M. Ando, Y. Taya, and M. Yamaizumi (2001)
J. Biol. Chem. 276, 39115-39122
   Abstract »    Full Text »    PDF »
Peptides from the amino terminal mdm-2-binding domain of p53, designed from conformational analysis, are selectively cytotoxic to transformed cells.
M. Kanovsky, A. Raffo, L. Drew, R. Rosal, T. Do, F. K. Friedman, P. Rubinstein, J. Visser, R. Robinson, P. W. Brandt-Rauf, et al. (2001)
PNAS
   Abstract »    Full Text »    PDF »
Dual Roles of RNA Helicase A in CREB-Dependent Transcription.
S. Aratani, R. Fujii, T. Oishi, H. Fujita, T. Amano, T. Ohshima, M. Hagiwara, A. Fukamizu, and T. Nakajima (2001)
Mol. Cell. Biol. 21, 4460-4469
   Abstract »    Full Text »    PDF »
The Corepressor mSin3a Interacts with the Proline-Rich Domain of p53 and Protects p53 from Proteasome-Mediated Degradation.
J. T. Zilfou, W. H. Hoffman, M. Sank, D. L. George, and M. Murphy (2001)
Mol. Cell. Biol. 21, 3974-3985
   Abstract »    Full Text »
Recruitment of the transcriptional machinery through GAL11P: structure and interactions of the GAL4 dimerization domain.
P. Hidalgo, A. Z. Ansari, P. Schmidt, B. Hare, N. Simkovich, S. Farrell, E. J. Shin, M. Ptashne, and G. Wagner (2001)
Genes & Dev. 15, 1007-1020
   Abstract »    Full Text »
Control of p53 Ubiquitination and Nuclear Export by MDM2 and ARF.
Y. Zhang and Y. Xiong (2001)
Cell Growth Differ. 12, 175-186
   Abstract »    Full Text »
Modeling multi-component protein-DNA complexes: the role of bending and dimerization in the complex of p53 dimers with DNA.
A. Lebrun, R. Lavery, and H. Weinstein (2001)
Protein Eng. Des. Sel. 14, 233-243
   Abstract »    Full Text »    PDF »
A Possible Role of p73 on the Modulation of p53 Level through MDM2.
X. Q. Wang, W. M. Ongkeko, A. W. S. Lau, K. M. Leung, and R. Y. C. Poon (2001)
Cancer Res. 61, 1598-1603
   Abstract »    Full Text »


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