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EGCG binds intrinsically disordered N-terminal domain of p53 and disrupts p53-MDM2 interaction

Author

Listed:
  • Jing Zhao

    (China Agricultural University
    Rensselaer Polytechnic Institute)

  • Alan Blayney

    (SUNY Upstate Medical University)

  • Xiaorong Liu

    (University of Massachusetts)

  • Lauren Gandy

    (Rensselaer Polytechnic Institute)

  • Weihua Jin

    (Rensselaer Polytechnic Institute)

  • Lufeng Yan

    (Rensselaer Polytechnic Institute)

  • Jeung-Hoi Ha

    (SUNY Upstate Medical University)

  • Ashley J. Canning

    (SUNY Upstate Medical University)

  • Michael Connelly

    (SUNY Upstate Medical University)

  • Chao Yang

    (New York University)

  • Xinyue Liu

    (Rensselaer Polytechnic Institute)

  • Yuanyuan Xiao

    (Rensselaer Polytechnic Institute)

  • Michael S. Cosgrove

    (SUNY Upstate Medical University)

  • Sozanne R. Solmaz

    (State University of New York at Binghamton)

  • Yingkai Zhang

    (New York University
    NYU-ECNU Center for Computational Chemistry at NYU Shanghai)

  • David Ban

    (Mass Spectrometry and Biophysics)

  • Jianhan Chen

    (University of Massachusetts
    University of Massachusetts)

  • Stewart N. Loh

    (SUNY Upstate Medical University)

  • Chunyu Wang

    (Rensselaer Polytechnic Institute)

Abstract

Epigallocatechin gallate (EGCG) from green tea can induce apoptosis in cancerous cells, but the underlying molecular mechanisms remain poorly understood. Using SPR and NMR, here we report a direct, μM interaction between EGCG and the tumor suppressor p53 (KD = 1.6 ± 1.4 μM), with the disordered N-terminal domain (NTD) identified as the major binding site (KD = 4 ± 2 μM). Large scale atomistic simulations (>100 μs), SAXS and AUC demonstrate that EGCG-NTD interaction is dynamic and EGCG causes the emergence of a subpopulation of compact bound conformations. The EGCG-p53 interaction disrupts p53 interaction with its regulatory E3 ligase MDM2 and inhibits ubiquitination of p53 by MDM2 in an in vitro ubiquitination assay, likely stabilizing p53 for anti-tumor activity. Our work provides insights into the mechanisms for EGCG’s anticancer activity and identifies p53 NTD as a target for cancer drug discovery through dynamic interactions with small molecules.

Suggested Citation

  • Jing Zhao & Alan Blayney & Xiaorong Liu & Lauren Gandy & Weihua Jin & Lufeng Yan & Jeung-Hoi Ha & Ashley J. Canning & Michael Connelly & Chao Yang & Xinyue Liu & Yuanyuan Xiao & Michael S. Cosgrove & , 2021. "EGCG binds intrinsically disordered N-terminal domain of p53 and disrupts p53-MDM2 interaction," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21258-5
    DOI: 10.1038/s41467-021-21258-5
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    Cited by:

    1. John C. K. Wang & Hannah T. Baddock & Amirhossein Mafi & Ian T. Foe & Matthew Bratkowski & Ting-Yu Lin & Zena D. Jensvold & Magdalena Preciado López & David Stokoe & Dan Eaton & Qi Hao & Aaron H. Nile, 2024. "Structure of the p53 degradation complex from HPV16," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Dilraj Lama & Thibault Vosselman & Cagla Sahin & Judit Liaño-Pons & Carmine P. Cerrato & Lennart Nilsson & Kaare Teilum & David P. Lane & Michael Landreh & Marie Arsenian Henriksson, 2024. "A druggable conformational switch in the c-MYC transactivation domain," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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