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Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX
- Source :
- Proceedings of the National Academy of Sciences. 106:4665-4670
- Publication Year :
- 2009
- Publisher :
- Proceedings of the National Academy of Sciences, 2009.
-
Abstract
- The oncoproteins MDM2 and MDMX negatively regulate the activity and stability of the tumor suppressor protein p53—a cellular process initiated by MDM2 and/or MDMX binding to the N-terminal transactivation domain of p53. MDM2 and MDMX in many tumors confer p53 inactivation and tumor survival, and are important molecular targets for anticancer therapy. We screened a duodecimal peptide phage library against site-specifically biotinylated p53-binding domains of human MDM2 and MDMX chemically synthesized via native chemical ligation, and identified several peptide inhibitors of the p53-MDM2/MDMX interactions. The most potent inhibitor (TSFAEYWNLLSP), termed PMI, bound to MDM2 and MDMX at low nanomolar affinities—approximately 2 orders of magnitude stronger than the wild-type p53 peptide of the same length (ETFSDLWKLLPE). We solved the crystal structures of synthetic MDM2 and MDMX, both in complex with PMI, at 1.6 Å resolution. Comparative structural analysis identified an extensive, tightened intramolecular H-bonding network in bound PMI that contributed to its conformational stability, thus enhanced binding to the 2 oncogenic proteins. Importantly, the C-terminal residue Pro of PMI induced formation of a hydrophobic cleft in MDMX previously unseen in the structures of p53-bound MDM2 or MDMX. Our findings deciphered the structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX, shedding new light on structure-based rational design of different classes of p53 activators for potential therapeutic use.
- Subjects :
- Models, Molecular
MDMX
Molecular Sequence Data
Cell Cycle Proteins
Peptide
Plasma protein binding
Biology
Protein Structure, Secondary
Structure-Activity Relationship
Protein structure
Peptide Library
Proto-Oncogene Proteins
Humans
Amino Acid Sequence
Peptide library
Peptide sequence
chemistry.chemical_classification
Multidisciplinary
Rational design
Nuclear Proteins
Proto-Oncogene Proteins c-mdm2
Biological Sciences
Native chemical ligation
Cell biology
chemistry
Biochemistry
Tumor Suppressor Protein p53
Peptides
Oligopeptides
Protein Binding
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 106
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....ce2c7a55de62b96a455d9773656f5be2