Structure of the human Mdmx protein bound to the p53 tumor suppressor transactivation domain. Cell Cycle 7:2441-2443

Cell cycle (Georgetown, Tex.) (Impact Factor: 4.57). 09/2008; 7(15):2441-3. DOI: 10.4161/cc.6365
Source: PubMed


The Mdmx oncoprotein has only recently emerged as a critical-independent to Mdm2-regulator of p53 activation. We have determined the crystal structure of the N-terminal domain of human Mdmx bound to a 15-residue transactivation domain peptide of human p53. The structure shows why antagonists of the Mdm2 binding to p53 are ineffective in the Mdmx-p53 interaction.

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    • "Specifically, targeting the interactions of p53 with its major negative regulators, MDM2 and MDM4, recently emerged as an important therapeutic approach, with multiple examples of both, small molecules and peptides being utilized as p53-MDM2/MDM4 inhibitors (Li and Lozano 2013; Saha et al. 2013; Wang et al. 2012; Zhao et al. 2013). p53-MDM2/MDM4 interactions are mediated primarily by three key hydrophobic residues in p53: 19 Phe, 23 Trp, and 26 Leu (Kussie et al. 1996; Pazgier et al. 2009; Popowicz et al. 2008), and similar though not identical, hydrophobic surface grooves in MDM2 and MDM4 (Zhao et al. 2013). Over past few years, mutational studies and phage display has produced multiple peptide-based p53–MDM2/MDMX inhibitors, including all-D, stapled and bridged compounds with increased resistance to proteolysis (Bernal et al. 2007, 2010; Chang et al. 2013; Guo et al. 2014; Hu et al. 2007; Li et al. 2009, 2010a, b; Madden et al. 2011; Madhumalar et al. 2009; Pazgier et al. 2009; Zhan et al. 2012). "
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    ABSTRACT: A small library of anticancer, cell-permeating, stapled peptides based on potent dual-specific antagonist of p53–MDM2/MDMX interactions, PMI-N8A, was synthesized, characterized and screened for anticancer activity against human colorectal cancer cell line, HCT-116. Employed synthetic modifications included: S-alkylation-based stapling, point mutations increasing hydrophobicity in key residues as well as improvement of cell-permeability by introduction of polycationic sequence(s) that were woven into the sequence of parental peptide. Selected analogue, ArB14Co, was also tested in vivo and exhibited potent anticancer bioactivity at the low dose (3.0 mg/kg). Collectively, our findings suggest that application of stapling in combination with rational design of polycationic short analogues may be a suitable approach in the development of physiologically active p53–MDM2/MDMX peptide inhibitors.
    International Journal of Peptide Research and Therapeutics 08/2015; DOI:10.1007/s10989-015-9487-3 · 0.91 Impact Factor
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    • "The p53 protein is composed of 393 residues and is divisible into three structural domains. The amino-terminal trans-activation domain, the central ‘core’ domain (residues from 102 to 292) that is essential for sequence-specific DNA binding and the carboxyl terminus oligomerization domain, which is required for the assembly of p53 tetramers and contains nuclear localization signals.5 The interaction of HBx protein and p53 tumor suppressor protein has been the subject of examinations in many researches in order to evaluate the biological function of p53 protein in HBV infected cells.14-16 "
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    ABSTRACT: Background: The ability of tumour suppressor protein p53 (P53) to regulate cell cycle processes can be modulated by hepatitis B virus (HBV). While preliminary evidences indicates the involvement of protein-x of HBV (HBx) in altering p53 DNA binding, no further data have been accumulated for the significance of serum p53 in chronic hepatitis B virus infected patients. Methods: 72 non-cirrhotic and 19 cirrhotic patients infected by HBV were enrolled for the analysis in this study. Enzyme linked immunosorbent assay (ELISA) was performed to study the concentrations of serum p53 protein. The tertiary structures of HBx and P53 were docked by Z-dock and Hex servers for in-silico protein-protein interaction analysis. Results: There was a significant association between the serum p53 and cirrhosis (OR=1.81 95% CI: 1.017-3.2, P=0.044). Cirrhotic patients had higher level of serum p53 compare with chronic infection of HBV (1.98±1.22 vs. 1.29±0.72 U/ml, P=0.05). No evidence of correlation was seen between the different variables such as age, gender, log viral load, serum alkaline phosphatase (ALP) and alanine aminotransferase (ALT) with serum p53. Tertiary model shows that the amino acid residues from Arg110 to Lys132 of the N-terminal of P53 which is critical for ubiquitination, are bonded to a region in N- terminal of HBx amino acid residues from Arg19 to Ser33. Conclusion: There is an increase in serum p53 in HBV-related cirrhosis patients. In this case, HBx might be responsible for such higher concentration of p53 through HBx-p53 protein-protein interaction, as is shown by molecular modeling approach.
    Iranian Journal of Medical Sciences 09/2014; 39(5):446-51.
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    • "MDMX is overexpressed in several cancers and it heterodimerizes to MDM2 via its RING finger domain at its C-terminus[85],[89],[90], thereby modulating its E3 ligase activity. MDM2 and MDMX are proposed to form a complex that is more effective at inhibiting p53 transactivation or enhancing p53 turnover[84]–[87],[90],[91]. MDM2 can also directly ubiquitinate and degrade MDMX upon DNA-damage stimuli[86]. "
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    ABSTRACT: The p53 tumor suppressor is a key transcription factor regulating cellular pathways such as DNA repair, cell cycle, apoptosis, angiogenesis, and senescence. It acts as an important defense mechanism against cancer onset and progression, and is negatively regulated by interaction with the oncoprotein MDM2. In human cancers, the TP53 gene is frequently mutated or deleted, or the wild-type p53 function is inhibited by high levels of MDM2, leading to downregulation of tumor suppressive p53 pathways. Thus, the inhibition of MDM2-p53 interaction presents an appealing therapeutic strategy for the treatment of cancer. However, recent studies have revealed the MDM2-p53 interaction to be more complex involving multiple levels of regulation by numerous cellular proteins and epigenetic mechanisms, making it imperative to reexamine this intricate interplay from a holistic viewpoint. This review aims to highlight the multifaceted network of molecules regulating the MDM2-p53 axis to better understand the pathway and exploit it for anticancer therapy.
    07/2013; 27(4):254-71. DOI:10.7555/JBR.27.20130030
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