Functional Interrogation of the N-Terminal Lid of MDMX in p53 Binding via Native Chemical Ligation

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  • Chen Xishan
    Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education China State Institute of Pharmaceutical Industry, Zhangjiang Institute
  • Lu Weiyue
    Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education

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  • Functional Interrogation of the N-Terminal Lid of MDMX in p53 Binding <i>via</i> Native Chemical Ligation

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The homologous proteins MDM2 and MDMX negatively regulate the tumor suppressor protein p53 by antagonizing p53 transactivation activity and targeting p53 for degradation. MDM2 and MDMX bind to p53 via N-terminal p53-binding domains to control the level of p53. The N-terminal regions of MDM2 and MDMX are modified in vivo under stressed conditions, suggesting that modifications to MDM2/MDMX also may affect the p53-MDM2/MDMX interaction. Ample evidence suggests that the MDM2 lid (residues 1–24) is partially structured and significantly reduces its binding affinity with p53 several fold. Since MDM2 and MDMX possess very similar p53-binding domains but different lids, however, the function of the N-terminal lid of MDMX still remains poorly understood. Using a native chemical ligation technique, the p53-binding domain of MDMX, (1–108)MDMX, and its N-terminal lid (residues 1–23) truncated analogue (24–108)MDMX were chemically synthesized. We comparatively characterized their structures by circular dichroism (CD) spectra, and measured their binding affinities with a panel of p53-derived peptide ligands by fluorescence polarization and surface plasmon resonance assays. Our results indicate that, as opposed to the lid of MDM2, the lid of MDMX has little effect on p53-binding, adopts no structural conformation, and has rare auto-inhibitory function. Different lid modifications of MDM2 and MDMX are functionally different with respect to p53 binding, which should be considered when designing dual specific inhibitors of MDM2 and MDMX.

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