Crystallographic analysis of an 8-mer p53 peptide analogue complexed with MDM2.
The most potent inhibitor of the p53-MDM2 interaction reported to date is an 8-mer p53 peptide analogue (Novartis peptide), which contains 6-chlorotryptophane (Cl-Trp) and phosphonomethylphenylalanine (Pmp) as key residues for the enhanced activity. We report here a crystal structure of the co-complex between MDM2 and the Novartis peptide solved at 1.8 A resolution. The structural basis for the role of the two aromatic residues are delineated by comparing the present structure with crystal structures of the MDM2 co-complex bound to other inhibitors including the wt-p53 peptide itself.
Sakurai
Kaori
K
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.
Schubert
Carsten
C
Kahne
Daniel
D
D018360:Crystallography, X-Ray; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry*; D011487:Protein Conformation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry*; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry*
D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2