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

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, Sozanne R. Solmaz, Yingkai Zhang, David Ban, Jianhan Chen, Stewart N. Loh and Chunyu Wang ()
Additional contact information
Jing Zhao: China Agricultural University
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
David Ban: Mass Spectrometry and Biophysics
Jianhan Chen: University of Massachusetts
Stewart N. Loh: SUNY Upstate Medical University
Chunyu Wang: Rensselaer Polytechnic Institute

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21258-5

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