3fdo | pdb_00003fdo

Structure of human MDMX in complex with high affinity peptide

spinqualitylabelsall models 3fdo, resolution 1.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3fdo is a 2 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.4Å Ligands: MG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function MDM4_HUMAN Inhibits p53/TP53- and TP73/p73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Inhibits degradation of MDM2. Can reverse MDM2-targeted degradation of TP53 while maintaining suppression of TP53 transactivation and apoptotic functions. 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 PubMed The 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also MDM4

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