NF-Y is a transcription factor (TF) comprising three subunits (NF-YA, NF-YB, NF-YC) that binds with high specificity to the CCAAT sequence, a widespread regulatory element in gene promoters of prosurvival, cell-cycle-promoting, and metabolic genes. Tumor cells undergo "metabolic rewiring" through overexpression of genes involved in such pathways, many of which are under NF-Y control. In addition, NF-YA appears to be overexpressed in many tumor types. Thus, limiting NF-Y activity may represent a desirable anti-cancer strategy, which is an ongoing field of research. With virtual-screening docking simulations on a library of pharmacologically active compounds, we identified suramin as a potential NF-Y inhibitor. We focused on suramin given its high water-solubility that is an important factor for in vitro testing, since NF-Y is sensitive to DMSO. By electrophoretic mobility shift assays (EMSA), isothermal titration calorimetry (ITC), STD NMR, X-ray crystallography, and molecular dynamics (MD) simulations, we showed that suramin binds to the histone fold domains (HFDs) of NF-Y, preventing DNA-binding. Our analyses, provide atomic-level detail on the interaction between suramin and NF-Y and reveal a region of the protein, nearby the suramin-binding site and poorly conserved in other HFD-containing TFs, that may represent a promising starting point for rational design of more specific and potent inhibitors with potential therapeutic applications.
Structural Basis of Inhibition of the Pioneer Transcription Factor NF-Y by Suramin / V. Nardone, A. Chaves-Sanjuan, M. Lapi, C. Airoldi, A. Saponaro, S. Pasqualato, D. Dolfini, C. Camilloni, A. Bernardini, N. Gnesutta, R. Mantovani, M. Nardini. - In: CELLS. - ISSN 2073-4409. - 9:11(2020 Oct).
|Titolo:||Structural Basis of Inhibition of the Pioneer Transcription Factor NF-Y by Suramin|
NARDONE, VALENTINA (Co-primo)
CHAVES SANJUAN, ANTONIO (Co-primo)
LAPI, MICHELA (Co-primo)
AIROLDI, CHIARA (Secondo)
MANTOVANI, ROBERTO (Penultimo)
NARDINI, MARCO (Ultimo) (Corresponding)
|Parole Chiave:||CCAAT box; histone fold; inhibition; NF-Y; suramin; transcription factor|
|Settore Scientifico Disciplinare:||Settore BIO/10 - Biochimica|
|Progetto:||CONSTANS companions: imparting sequence-specificity to histone-like proteins in plants|
|Data di pubblicazione:||ott-2020|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.3390/cells9112370|
|Appare nelle tipologie:||01 - Articolo su periodico|