Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. 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.
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.
Deregulation of c-MYC can occur through elevated transcription of the gene, amplification, chromosomal translocation, point mutation, or protein stabilization, all of which release the otherwise tight control and increase expression levels of the protein in the cell 1 , 5. Inhibition of c-MYC, on the other hand, has been observed to promote apoptosis, growth arrest, differentiation, senescence, metabolic changes, as well as tumour regression in several human cancer models, clearly indicating its potential as a target for anti-cancer therapeutics 6 , 7 , 8 , 9.
Targeting c-MYC using traditional structure-based drug design has remained challenging, due to its lack of a stable tertiary fold Intrinsically disordered proteins IDPs like c-MYC exist in an ensemble of conformational states, which facilitate their interaction with multiple binding partners.
