Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain Journal Article
| Authors: | Kussie, P. H.; Gorina, S.; Marechal, V.; Elenbaas, B.; Moreau, J.; Levine, A. J.; Pavletich, N. P. |
| Article Title: | Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain |
| Abstract: | 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 α helix. The interface relies on the steric complementarity between the MDM2 cleft and the hydrophobic face of the p53 α 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 α helix may be a common structural motif in the binding of a diverse family of transactivation factors to the TATA-binding protein-associated factors. 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 α helix. The interface relies on the steric complementarity between the MDM2 cleft and the hydrophobic face of the p53 α 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 α helix may be a common structural motif in the binding of a diverse family of transactivation factors to the TATA-binding protein-associated factors. |
| Keywords: | controlled study; oncoprotein; proto-oncogene proteins; nonhuman; protein conformation; protein domain; proteins; genes; gene amplification; gene expression; protein protein interaction; protein binding; transcription factor; protein p53; transcription factors; nuclear proteins; tumor suppressor gene; dna; amino terminal sequence; gene repression; transactivation; tumor suppressor protein p53; crystal structure; hydrogen bonding; models, molecular; crystallography, x-ray; protein structure, tertiary; binding sites; amino acids; protein folding; protein structure; crystallization; protein structure, secondary; diseases; dna sequences; proto-oncogene proteins c-mdm2; xenopus laevis; cells; dna protein complex; hydrophobicity; cancers; trans-activation (genetics); tata binding protein; human; priority journal; article; cellular inhibitor; tumor suppressor transactivation domain |
| Journal Title: | Science |
| Volume: | 274 |
| Issue: | 5289 |
| ISSN: | 0036-8075 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 1996-11-08 |
| Start Page: | 948 |
| End Page: | 953 |
| Language: | English |
| DOI: | 10.1126/science.274.5289.948 |
| PUBMED: | 8875929 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Export Date: 22 November 2017 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work