Structural Basis of Inhibition of the Pioneer Transcription Factor NF-Y by Suramin

• Published in: Cells (Basel, Switzerland) Vol. 9; no. 11; p. 2370
• Main Authors: Nardone, Valentina, Chaves-Sanjuan, Antonio, Lapi, Michela, Airoldi, Cristina, Saponaro, Andrea, Pasqualato, Sebastiano, Dolfini, Diletta, Camilloni, Carlo, Bernardini, Andrea, Gnesutta, Nerina, Mantovani, Roberto, Nardini, Marco
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 29.10.2020; MDPI
• Subjects: Amino Acid Sequence; Biophysical Phenomena; CCAAT box; CCAAT-Binding Factor - antagonists & inhibitors; CCAAT-Binding Factor - chemistry; DNA - metabolism; Dosage and administration; histone fold; Humans; inhibition; Magnetic Resonance Spectroscopy; Molecular Dynamics Simulation; NF-Y; Physiological aspects; Protein Multimerization; Structure; Structure-Activity Relationship; suramin; Suramin - chemistry; Suramin - pharmacology; Suramin sodium; transcription factor; Transcription factors; Transcription Factors - antagonists & inhibitors; Transcription Factors - chemistry; Italy; NF-Y; CCAAT box; transcription factor; histone fold; inhibition; suramin
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells9112370

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.