Abstract
AbstractEpigallocatechin 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.
Funder
U.S. Department of Health & Human Services | National Institutes of Health
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
Reference83 articles.
1. Du, G. J. et al. Epigallocatechin gallate (EGCG) is the most effective cancer chemopreventive polyphenol in green tea. Nutrients 4, 1679–1691 (2012).
2. Khan, N., Afaq, F., Saleem, M., Ahmad, N. & Mukhtar, H. Targeting multiple signaling pathways by green tea polyphenol (-)-epigallocatechin-3-gallate. Cancer Res. 66, 2500–2505 (2006).
3. Lee, M. J. et al. Analysis of plasma and urinary tea polyphenols in human subjects. Cancer Epidemiol. Biomark. Prev. 4, 393–399 (1995).
4. Lambert, J. D. & Yang, C. S. Cancer chemopreventive activity and bioavailability of tea and tea polyphenols. Mutat. Res.—Fundam. Mol. Mech. Mutagen. 523–524, 201–208 (2003).
5. Gan, R.-Y., Li, H.-B., Sui, Z.-Q. & Corke, H. Absorption, metabolism, anti-cancer effect and molecular targets of epigallocatechin gallate (EGCG): an updated review. Crit. Rev. Food Sci. Nutr. 8398, 1–18 (2016).
Cited by
84 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献