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; Chunyu Wang

doi:10.1038/s41467-021-21258-5

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, Chunyu Wang

Chemistry

Research output: Contribution to journal › Article › peer-review

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 (K_D = 1.6 ± 1.4 μM), with the disordered N-terminal domain (NTD) identified as the major binding site (K_D = 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.

Original language	English (US)
Article number	986
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-21258-5
State	Published - Dec 1 2021

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Zhao, J., Blayney, A., Liu, X., Gandy, L., Jin, W., Yan, L., Ha, J. H., Canning, A. J., Connelly, M., Yang, C., Liu, X., Xiao, Y., Cosgrove, M. S., Solmaz, S. R., Zhang, Y., Ban, D., Chen, J., Loh, S. N., & Wang, C. (2021). EGCG binds intrinsically disordered N-terminal domain of p53 and disrupts p53-MDM2 interaction. Nature communications, 12(1), Article 986. https://doi.org/10.1038/s41467-021-21258-5

Zhao, J, Blayney, A, Liu, X, Gandy, L, Jin, W, Yan, L, Ha, JH, Canning, AJ, Connelly, M, Yang, C, Liu, X, Xiao, Y, Cosgrove, MS, Solmaz, SR, Zhang, Y, Ban, D, Chen, J, Loh, SN & Wang, C 2021, 'EGCG binds intrinsically disordered N-terminal domain of p53 and disrupts p53-MDM2 interaction', Nature communications, vol. 12, no. 1, 986. https://doi.org/10.1038/s41467-021-21258-5

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title = "EGCG binds intrinsically disordered N-terminal domain of p53 and disrupts p53-MDM2 interaction",

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{\textquoteright}s anticancer activity and identifies p53 NTD as a target for cancer drug discovery through dynamic interactions with small molecules.",

author = "Jing Zhao and Alan Blayney and Xiaorong Liu and Lauren Gandy and Weihua Jin and Lufeng Yan and Ha, {Jeung Hoi} and Canning, {Ashley J.} and Michael Connelly and Chao Yang and Xinyue Liu and Yuanyuan Xiao and Cosgrove, {Michael S.} and Solmaz, {Sozanne R.} and Yingkai Zhang and David Ban and Jianhan Chen and Loh, {Stewart N.} and Chunyu Wang",

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AU - Zhao, Jing

AU - Blayney, Alan

AU - Liu, Xiaorong

AU - Gandy, Lauren

AU - Jin, Weihua

AU - Yan, Lufeng

AU - Ha, Jeung Hoi

AU - Canning, Ashley J.

AU - Connelly, Michael

AU - Yang, Chao

AU - Liu, Xinyue

AU - Xiao, Yuanyuan

AU - Cosgrove, Michael S.

AU - Solmaz, Sozanne R.

AU - Zhang, Yingkai

AU - Ban, David

AU - Chen, Jianhan

AU - Loh, Stewart N.

AU - Wang, Chunyu

PY - 2021/12/1

Y1 - 2021/12/1

N2 - 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.

AB - 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.

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

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