A druggable conformational switch in the c-MYC transactivation domain

Dilraj Lama (), Thibault Vosselman, Cagla Sahin, Judit Liaño-Pons, Carmine P. Cerrato, Lennart Nilsson, Kaare Teilum, David P. Lane, Michael Landreh () and Marie Arsenian Henriksson ()
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Dilraj Lama: Karolinska Institutet, Biomedicum
Thibault Vosselman: Karolinska Institutet, Biomedicum
Cagla Sahin: Karolinska Institutet, Biomedicum
Judit Liaño-Pons: Karolinska Institutet, Biomedicum
Carmine P. Cerrato: Karolinska Institutet, Biomedicum
Lennart Nilsson: Karolinska Institutet
Kaare Teilum: University of Copenhagen
David P. Lane: Karolinska Institutet, Biomedicum
Michael Landreh: Karolinska Institutet, Biomedicum
Marie Arsenian Henriksson: Karolinska Institutet, Biomedicum

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-45826-7

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