AbstractThe c-MYC oncogene is activated in over 70% of all human cancers. The intrinsic disorder of the c-MYC transcription factor facilitates molecular interactions that regulate numerous biological pathways, but severely limits efforts to target its function for cancer therapy. Here, we use a reductionist strategy to characterize the dynamic and structural heterogeneity of the c-MYC protein. Using probe-based Molecular Dynamics (MD) simulations and machine learning, we identify a conformational switch in the c-MYC amino-terminal transactivation domain (termed coreMYC) that cycles between a closed, inactive, and an open, active conformation. Using the polyphenol epigallocatechin gallate (EGCG) to modulate the conformational landscape of coreMYC, we show through biophysical and cellular assays that the induction of a closed conformation impedes its interactions with the transformation/transcription domain-associated protein (TRRAP) and the TATA-box binding protein (TBP) which are essential for the transcriptional and oncogenic activities of c-MYC. Together, these findings provide insights into structure-activity relationships of c-MYC, which open avenues towards the development of shape-shifting compounds to target c-MYC as well as other disordered transcription factors for cancer treatment.