A druggable conformational switch in the c-MYC transactivation domain
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A druggable conformational switch in the c-MYC transactivation domain. / Lama, Dilraj; Vosselman, Thibault; Sahin, Cagla; Liaño-pons, Judit; Cerrato, Carmine P.; Nilsson, Lennart; Teilum, Kaare; Lane, David P.; Landreh, Michael; Arsenian Henriksson, Marie.
I: Nature Communications, Bind 15, Nr. 1, 1865, 2024.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - A druggable conformational switch in the c-MYC transactivation domain
AU - Lama, Dilraj
AU - Vosselman, Thibault
AU - Sahin, Cagla
AU - Liaño-pons, Judit
AU - Cerrato, Carmine P.
AU - Nilsson, Lennart
AU - Teilum, Kaare
AU - Lane, David P.
AU - Landreh, Michael
AU - Arsenian Henriksson, Marie
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-024-45826-7
DO - 10.1038/s41467-024-45826-7
M3 - Journal article
VL - 15
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1865
ER -
ID: 383933929