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, ?M interaction between EGCG and the tumor suppressor p53 (K_D?=?1.6?±?1.4 ?M), with the disordered N-terminal domain (NTD) identified as the major binding site (K_D?=?4?±?2 ?M). Large scale atomistic simulations (>100 ?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.

SUBMITTER: Zhao J 

PROVIDER: S-EPMC7881117 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature