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 Nov), pp. 2370.1-2370.21. [10.3390/cells9112370]

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

V. Nardone
Co-primo
;
A. Chaves-Sanjuan
Co-primo
;
M. Lapi
Co-primo
;
A. Saponaro;D. Dolfini;C. Camilloni;A. Bernardini;N. Gnesutta;R. Mantovani
Penultimo
;
M. Nardini
Ultimo
2020

Abstract

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.
CCAAT box; histone fold; inhibition; NF-Y; suramin; transcription factor
Settore BIO/10 - Biochimica
Settore FIS/07 - Fisica Applicata(Beni Culturali, Ambientali, Biol.e Medicin)
   CONSTANS companions: imparting sequence-specificity to histone-like proteins in plants
   MINISTERO DELL'ISTRUZIONE E DEL MERITO
   2017SBFHLH_001
nov-2020
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/793521
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