Structural analysis of MDM2 RING separates degradation from regulation of p53 transcription activity
| Autor: | Karen H. Vousden, Marta Klejnot, Gary J. Sibbet, Dominika Kowalczyk, Danny T. Huang, Andreas K. Hock, Koji Nomura |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Models Molecular Transcription Genetic Protein Conformation Cell Cycle Proteins Crystallography X-Ray Article 03 medical and health sciences Structural Biology Transcription (biology) Proto-Oncogene Proteins Ring domain Molecular Biology neoplasms chemistry.chemical_classification Transcriptional activity DNA ligase biology Nuclear Proteins Proto-Oncogene Proteins c-mdm2 3. Good health Cell biology 030104 developmental biology chemistry Proteolysis Ubiquitin-Conjugating Enzymes biology.protein Mdm2 Mutant Proteins Tumor Suppressor Protein p53 Protein Binding |
| Zdroj: | Nature Structural & Molecular Biology |
| ISSN: | 1545-9993 |
| DOI: | 10.1038/nsmb.3414 |
| Popis: | MDM2-MDMX complexes bind the p53 tumor suppressor protein, inhibiting p53’s transcriptional activity and targeting p53 for proteasomal degradation. Inhibitors that disrupt binding between p53 and MDM2 efficiently activate a p53 response although their use in the treatment of cancers that retain wild type p53 may be limited by on-target toxicities due to p53 activation in normal tissue. Guided by a novel crystal structure of the MDM2-MDMX-E2(UbcH5B)–ubiquitin complex, we designed MDM2 mutants that prevent E2–ubiquitin binding without altering the RING domain structure. These mutants lose MDM2’s E3 activity, but retain the ability to limit p53's transcriptional activity and allow cell proliferation. Cells expressing these mutants responded more quickly to cellular stress than cells expressing wild type MDM2. Targeting the MDM2 E3 ligase activity could widen the therapeutic window of p53 activation in tumors, since rapid p53 induction can be achieved while basal p53 control by MDM2 is maintained. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink