7AH8

NF-Y bound to suramin inhibitor

Summary for 7AH8

• Entry DOI: 10.2210/pdb7ah8/pdb
• Descriptor: Nuclear transcription factor Y subunit beta, Isoform 6 of Nuclear transcription factor Y subunit gamma, GLYCEROL, ... (6 entities in total)
• Functional Keywords: transcription factor, nf-y, hfd, inhibitor, suramin, transcription
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 40719.98

Authors

Nardone, V.,Chaves-Sanjuan, A.,Lapi, M.,Nardini, M. (deposition date: 2020-09-24, release date: 2021-08-04, Last modification date: 2024-01-31)

Primary citation

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.
Structural Basis of Inhibition of the Pioneer Transcription Factor NF-Y by Suramin.
Cells, 9:-, 2020

PubMed 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.

PubMed: 33138093
DOI: 10.3390/cells9112370

Experimental method

X-RAY DIFFRACTION (2.70001356517 Å)