EGCG binds intrinsically disordered N-terminal domain of p53 and disrupts p53-MDM2 interaction.
Nat Commun
; 12(1): 986, 2021 02 12.
Article
em En
| MEDLINE
| ID: mdl-33579943
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's anticancer activity and identifies p53 NTD as a target for cancer drug discovery through dynamic interactions with small molecules.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Catequina
/
Proteína Supressora de Tumor p53
/
Apoptose
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Proteínas Proto-Oncogênicas c-mdm2
Limite:
Humans
Idioma:
En
Revista:
Nat Commun
Ano de publicação:
2021
Tipo de documento:
Article