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

Author:

Zhao Jing,Blayney AlanORCID,Liu Xiaorong,Gandy Lauren,Jin Weihua,Yan Lufeng,Ha Jeung-Hoi,Canning Ashley J.,Connelly MichaelORCID,Yang Chao,Liu Xinyue,Xiao Yuanyuan,Cosgrove Michael S.,Solmaz Sozanne R.,Zhang YingkaiORCID,Ban David,Chen JianhanORCID,Loh Stewart N.,Wang ChunyuORCID

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).

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3