Title
EGCG binds intrinsically disordered N-terminal domain of p53 and disrupts p53-MDM2 interaction
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
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]
Recommended Citation
Chen, Jianhen; Zhao, Jing; Blayney, Alan; Liu, Xiaorong; Gandy, Lauren; Jin, Weihua; Yan, Lufeng; Ha, Jeung-Hoi; Canning, Ashley J.; and Connelly, Michael, "EGCG binds intrinsically disordered N-terminal domain of p53 and disrupts p53-MDM2 interaction" (2021). NATURE COMMUNICATIONS. 1488.
https://doi.org/10.1038/s41467-021-21258-5