Publication Date

2021

Journal or Book Title

NATURE COMMUNICATIONS

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, mu M interaction between EGCG and the tumor suppressor p53 (K-D=1.61.4 mu M), with the disordered N-terminal domain (NTD) identified as the major binding site (K-D=4 +/- 2 mu M). Large scale atomistic simulations (>100 mu s), 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. Epigallocatechin gallate (EGCG) is a catechin flavonoid which induces apoptosis in cancerous cells, but the underlying molecular mechanisms remain poorly understood. Here authors use an interdisciplinary approach to show a direct interaction between EGCG and the tumor suppressor p53 and demonstrate that EGCG inhibits ubiquitination of p53 by MDM2.

ISSN

2041-1723

ORCID

Liu, Xinyue/0000-0002-0934-4155; Blayney, Alan/0000-0003-0741-1550; Gandy, Lauren/0000-0001-7656-8186; Yang, Chao/0000-0002-7136-6013

DOI

https://doi.org/10.1038/s41467-021-21258-5

Volume

12

Issue

1

License

UMass Amherst Open Access Policy

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

Funder

NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01CA206592, R35-GM127040, R01CA140522, 1R15GM128119-01]; NIH-NIA Training Grant [T32AG057464]; NSFNational Science Foundation (NSF) [DMR-1829070]; NIH/NIGMSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [GM-124166]

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