3g03 | pdb_00003g03
Structure of human MDM2 in complex with high affinity peptide
Structural highlights
DiseaseMDM2_HUMAN Note=Seems to be amplified in certain tumors (including soft tissue sarcomas, osteosarcomas and gliomas). A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding. FunctionMDM2_HUMAN E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome. Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as an ubiquitin ligase E3 toward itself and ARRB1. Permits the nuclear export of p53/TP53. Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation. Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53. Also component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways. Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus. Ubiquitinates IGF1R and promotes it to proteasomal degradation.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe Mdm2 and Mdmx proteins are the principal negative regulators of the p53 tumor suppressor. Reactivation of p53 activity by disrupting the Mdm2/Mdmx-p53 interactions offers new possibilities for anticancer therapeutics. Here, we present crystal structures of two complexes, a p53-like mutant peptide with the N-terminal domains of Mdm2 and Mdmx, respectively. The structures reveal that the p53 mutant peptide (amino acid sequence: LTFEHYWAQLTS) assumes virtually identical conformations in both complexes despite the different shapes of the p53-binding pockets in these two proteins, has a more extended helical nature compared to the Mdm2-bound wild-type p53 peptide, and does not disturb the native folds of Mdm2 or Mdmx. The extension of the helical structure in the mutant p53 peptide greatly improves its binding to Mdm2 and Mdmx. The fluorescence polarization assay that we have developed using this peptide indicates the affinities towards Mdm2 of 3.6 nM and for Mdmx of 6.1 nM, compared to the low micromolar binding of a similar length wild-type p53 peptide to Mdm2/Mdmx. Our assay does not require expensive non-native amino acids, and allows measurements of the interaction with both Mdm2 and Mdmx in identical conditions-without modification of experimental conditions or setups between the two proteins. The structural information presented here, coupled with the robust fluorescence polarization assay, should enable development of a simple pharmacophore model of cross-selective Mdm2-Mdmx/p53 inhibitors. High affinity interaction of the p53 peptide-analogue with human Mdm2 and Mdmx.,Czarna A, Popowicz GM, Pecak A, Wolf S, Dubin G, Holak TA Cell Cycle. 2009 Apr 16;8(8). PMID:19305137[12] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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