A druggable conformational switch in the c-MYC transactivation domain

• Published in: Nature communications Vol. 15; no. 1; p. 1865
• Main Authors: Lama, Dilraj, Vosselman, Thibault, Sahin, Cagla, Liaño-Pons, Judit, Cerrato, Carmine P., Nilsson, Lennart, Teilum, Kaare, Lane, David P., Landreh, Michael, Arsenian Henriksson, Marie
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29-02-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 101/58; 119/118; 14/63; 631/57/2266; 631/67; 631/92; c-Myc protein; Cancer; Cancer therapies; Epigallocatechin gallate; Heterogeneity; Humanities and Social Sciences; Machine learning; Medicin och hälsovetenskap; Molecular dynamics; Molecular interactions; multidisciplinary; Myc protein; Protein structure; Proteins; Science; Science (multidisciplinary); Structure-activity relationships; TATA-binding protein; Transcription factors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-45826-7

The 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.
Here, the authors identify a conformational switch in the amino-terminal transactivation domain of c-MYC, termed coreMYC, which cycles between a closed, inactive state and an open, active conformation. Polyphenol epigallocatechin gallate (EGCG) is used to modulate the conformational landscape of coreMYC, stabilizing the closed and inactive conformation.