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Structural Basis of Inhibition of the Pioneer Transcription Factor NF-Y by Suramin
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 ov...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692634/ https://www.ncbi.nlm.nih.gov/pubmed/33138093 http://dx.doi.org/10.3390/cells9112370 |
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author | 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 |
author_facet | 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 |
author_sort | Nardone, Valentina |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7692634 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-76926342020-11-28 Structural Basis of Inhibition of the Pioneer Transcription Factor NF-Y by Suramin 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 Cells Article 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. MDPI 2020-10-29 /pmc/articles/PMC7692634/ /pubmed/33138093 http://dx.doi.org/10.3390/cells9112370 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article 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 Structural Basis of Inhibition of the Pioneer Transcription Factor NF-Y by Suramin |
title | Structural Basis of Inhibition of the Pioneer Transcription Factor NF-Y by Suramin |
title_full | Structural Basis of Inhibition of the Pioneer Transcription Factor NF-Y by Suramin |
title_fullStr | Structural Basis of Inhibition of the Pioneer Transcription Factor NF-Y by Suramin |
title_full_unstemmed | Structural Basis of Inhibition of the Pioneer Transcription Factor NF-Y by Suramin |
title_short | Structural Basis of Inhibition of the Pioneer Transcription Factor NF-Y by Suramin |
title_sort | structural basis of inhibition of the pioneer transcription factor nf-y by suramin |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692634/ https://www.ncbi.nlm.nih.gov/pubmed/33138093 http://dx.doi.org/10.3390/cells9112370 |
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