Cargando…
In Search of Small Molecule Inhibitors Targeting the Flexible CK2 Subunit Interface
Protein kinase CK2 is a tetrameric holoenzyme composed of two catalytic (α and/or α’) subunits and two regulatory (β) subunits. Crystallographic data paired with fluorescence imaging techniques have suggested that the formation of the CK2 holoenzyme complex within cells is a dynamic process. Althoug...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374420/ https://www.ncbi.nlm.nih.gov/pubmed/28165359 http://dx.doi.org/10.3390/ph10010016 |
_version_ | 1782518886702252032 |
---|---|
author | Bestgen, Benoît Belaid-Choucair, Zakia Lomberget, Thierry Le Borgne, Marc Filhol, Odile Cochet, Claude |
author_facet | Bestgen, Benoît Belaid-Choucair, Zakia Lomberget, Thierry Le Borgne, Marc Filhol, Odile Cochet, Claude |
author_sort | Bestgen, Benoît |
collection | PubMed |
description | Protein kinase CK2 is a tetrameric holoenzyme composed of two catalytic (α and/or α’) subunits and two regulatory (β) subunits. Crystallographic data paired with fluorescence imaging techniques have suggested that the formation of the CK2 holoenzyme complex within cells is a dynamic process. Although the monomeric CK2α subunit is endowed with a constitutive catalytic activity, many of the plethora of CK2 substrates are exclusively phosphorylated by the CK2 holoenzyme. This means that the spatial and high affinity interaction between CK2α and CK2β subunits is critically important and that its disruption may provide a powerful and selective way to block the phosphorylation of substrates requiring the presence of CK2β. In search of compounds inhibiting this critical protein–protein interaction, we previously designed an active cyclic peptide (Pc) derived from the CK2β carboxy-terminal domain that can efficiently antagonize the CK2 subunit interaction. To understand the functional significance of this interaction, we generated cell-permeable versions of Pc, exploring its molecular mechanisms of action and the perturbations of the signaling pathways that it induces in intact cells. The identification of small molecules inhibitors of this critical interaction may represent the first-choice approach to manipulate CK2 in an unconventional way. |
format | Online Article Text |
id | pubmed-5374420 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-53744202017-04-10 In Search of Small Molecule Inhibitors Targeting the Flexible CK2 Subunit Interface Bestgen, Benoît Belaid-Choucair, Zakia Lomberget, Thierry Le Borgne, Marc Filhol, Odile Cochet, Claude Pharmaceuticals (Basel) Article Protein kinase CK2 is a tetrameric holoenzyme composed of two catalytic (α and/or α’) subunits and two regulatory (β) subunits. Crystallographic data paired with fluorescence imaging techniques have suggested that the formation of the CK2 holoenzyme complex within cells is a dynamic process. Although the monomeric CK2α subunit is endowed with a constitutive catalytic activity, many of the plethora of CK2 substrates are exclusively phosphorylated by the CK2 holoenzyme. This means that the spatial and high affinity interaction between CK2α and CK2β subunits is critically important and that its disruption may provide a powerful and selective way to block the phosphorylation of substrates requiring the presence of CK2β. In search of compounds inhibiting this critical protein–protein interaction, we previously designed an active cyclic peptide (Pc) derived from the CK2β carboxy-terminal domain that can efficiently antagonize the CK2 subunit interaction. To understand the functional significance of this interaction, we generated cell-permeable versions of Pc, exploring its molecular mechanisms of action and the perturbations of the signaling pathways that it induces in intact cells. The identification of small molecules inhibitors of this critical interaction may represent the first-choice approach to manipulate CK2 in an unconventional way. MDPI 2017-02-03 /pmc/articles/PMC5374420/ /pubmed/28165359 http://dx.doi.org/10.3390/ph10010016 Text en © 2017 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 Bestgen, Benoît Belaid-Choucair, Zakia Lomberget, Thierry Le Borgne, Marc Filhol, Odile Cochet, Claude In Search of Small Molecule Inhibitors Targeting the Flexible CK2 Subunit Interface |
title | In Search of Small Molecule Inhibitors Targeting the Flexible CK2 Subunit Interface |
title_full | In Search of Small Molecule Inhibitors Targeting the Flexible CK2 Subunit Interface |
title_fullStr | In Search of Small Molecule Inhibitors Targeting the Flexible CK2 Subunit Interface |
title_full_unstemmed | In Search of Small Molecule Inhibitors Targeting the Flexible CK2 Subunit Interface |
title_short | In Search of Small Molecule Inhibitors Targeting the Flexible CK2 Subunit Interface |
title_sort | in search of small molecule inhibitors targeting the flexible ck2 subunit interface |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374420/ https://www.ncbi.nlm.nih.gov/pubmed/28165359 http://dx.doi.org/10.3390/ph10010016 |
work_keys_str_mv | AT bestgenbenoit insearchofsmallmoleculeinhibitorstargetingtheflexibleck2subunitinterface AT belaidchoucairzakia insearchofsmallmoleculeinhibitorstargetingtheflexibleck2subunitinterface AT lombergetthierry insearchofsmallmoleculeinhibitorstargetingtheflexibleck2subunitinterface AT leborgnemarc insearchofsmallmoleculeinhibitorstargetingtheflexibleck2subunitinterface AT filholodile insearchofsmallmoleculeinhibitorstargetingtheflexibleck2subunitinterface AT cochetclaude insearchofsmallmoleculeinhibitorstargetingtheflexibleck2subunitinterface |