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Article

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

by
Valentina Nardone
1,†,
Antonio Chaves-Sanjuan
1,†,
Michela Lapi
1,†,
Cristina Airoldi
2,
Andrea Saponaro
1,
Sebastiano Pasqualato
3,
Diletta Dolfini
1,
Carlo Camilloni
1,
Andrea Bernardini
1,
Nerina Gnesutta
1,
Roberto Mantovani
1 and
Marco Nardini
1,*
1
Department of Biosciences, University of Milano, Via Celoria 26, 20133 Milano, Italy
2
Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milan, Italy
3
Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Via Adamello 16, 20139 Milan, Italy
*
Author to whom correspondence should be addressed.
†
These authors equally contributed to the work.
Cells 2020, 9(11), 2370; https://doi.org/10.3390/cells9112370
Submission received: 28 September 2020 / Revised: 25 October 2020 / Accepted: 26 October 2020 / Published: 29 October 2020
(This article belongs to the Special Issue Metabolic Rewiring in Cancer Cells: From Tumor Onset to Novel Therapies)
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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.
Keywords: transcription factor; histone fold; CCAAT box; NF-Y; suramin; inhibition transcription factor; histone fold; CCAAT box; NF-Y; suramin; inhibition
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MDPI and ACS Style

Nardone, V.; Chaves-Sanjuan, A.; Lapi, M.; Airoldi, C.; Saponaro, A.; Pasqualato, S.; Dolfini, D.; Camilloni, C.; Bernardini, A.; Gnesutta, N.; et al. Structural Basis of Inhibition of the Pioneer Transcription Factor NF-Y by Suramin. Cells 2020, 9, 2370. https://doi.org/10.3390/cells9112370

AMA Style

Nardone V, Chaves-Sanjuan A, Lapi M, Airoldi C, Saponaro A, Pasqualato S, Dolfini D, Camilloni C, Bernardini A, Gnesutta N, et al. Structural Basis of Inhibition of the Pioneer Transcription Factor NF-Y by Suramin. Cells. 2020; 9(11):2370. https://doi.org/10.3390/cells9112370

Chicago/Turabian Style

Nardone, Valentina, Antonio Chaves-Sanjuan, Michela Lapi, Cristina Airoldi, Andrea Saponaro, Sebastiano Pasqualato, Diletta Dolfini, Carlo Camilloni, Andrea Bernardini, Nerina Gnesutta, and et al. 2020. "Structural Basis of Inhibition of the Pioneer Transcription Factor NF-Y by Suramin" Cells 9, no. 11: 2370. https://doi.org/10.3390/cells9112370

APA Style

Nardone, V., Chaves-Sanjuan, A., Lapi, M., Airoldi, C., Saponaro, A., Pasqualato, S., Dolfini, D., Camilloni, C., Bernardini, A., Gnesutta, N., Mantovani, R., & Nardini, M. (2020). Structural Basis of Inhibition of the Pioneer Transcription Factor NF-Y by Suramin. Cells, 9(11), 2370. https://doi.org/10.3390/cells9112370

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