A druggable conformational switch in the c-MYC transactivation domain

Area of Science:

• Oncology
• Molecular Biology
• Biophysics

Background:

• The c-MYC oncogene is frequently activated in human cancers.
• c-MYC's disordered nature aids function but hinders therapeutic targeting.

Purpose of the Study:

• To characterize the dynamic and structural heterogeneity of the c-MYC protein.
• To identify druggable conformational states of c-MYC for cancer therapy.

Main Methods:

• Utilized probe-based Molecular Dynamics (MD) simulations and machine learning.
• Employed biophysical and cellular assays to validate findings.
• Investigated the effect of epigallocatechin gallate (EGCG) on c-MYC conformation.

Main Results:

• Identified a conformational switch in coreMYC (c-MYC N-terminal domain) between active and inactive states.
• EGCG binding promotes a closed, inactive conformation of coreMYC.
• Inhibition of coreMYC closed conformation disrupts essential interactions with TRRAP and TBP.

Conclusions:

• Disordered transcription factors like c-MYC possess druggable conformational states.
• Modulating c-MYC conformation offers a novel therapeutic strategy for cancers.
• Shape-shifting compounds targeting c-MYC's dynamic landscape present a promising avenue for cancer treatment.