Modulation of the Allosteric Communication between the Polo-Box Domain and the Catalytic Domain in Plk1 by Small Compounds

Autores
Raab, Monika; Sanhaji, Mourad; Pietsch, Larissa; Béquignon, Isabelle; Herbrand, Amanda K.; Süß, Evelyn; Gande, Santosh L.; Caspar, Birgit; Kudlinzki, Denis; Saxena, Krishna; Sreeramulu, Sridhar; Schwalbe, Harald; Strebhardt, Klaus; Biondi, Ricardo Miguel
Año de publicación
2018
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The Polo-like kinases (Plks) are an evolutionary conserved family of Ser/Thr protein kinases that possess, in addition to the classical kinase domain at the N-terminus, a C-terminal polo-box domain (PBD) that binds to phosphorylated proteins and modulates the kinase activity and its localization. Plk1, which regulates the formation of the mitotic spindle, has emerged as a validated drug target for the treatment of cancer, because it is required for numerous types of cancer cells but not for the cell division in noncancer cells. Here, we employed chemical biology methods to investigate the allosteric communication between the PBD and the catalytic domain of Plk1. We identified small compounds that bind to the catalytic domain and inhibit or enhance the interaction of Plk1 with the phosphorylated peptide PoloBoxtide in vitro. In cells, two new allosteric Plk1 inhibitors affected the proliferation of cancer cells in culture and the cell cycle but had distinct phenotypic effects on spindle formation. Both compounds inhibited Plk1 signaling, indicating that they specifically act on Plk1 in cultured cells.
Fil: Raab, Monika. Goethe Universitat Frankfurt; Alemania
Fil: Sanhaji, Mourad. Goethe Universitat Frankfurt; Alemania
Fil: Pietsch, Larissa. German Cancer Research Center; Alemania. Goethe Universitat Frankfurt; Alemania
Fil: Béquignon, Isabelle. Goethe Universitat Frankfurt; Alemania
Fil: Herbrand, Amanda K.. Goethe Universitat Frankfurt; Alemania
Fil: Süß, Evelyn. Goethe Universitat Frankfurt; Alemania
Fil: Gande, Santosh L.. German Cancer Research Center; Alemania. Goethe Universitat Frankfurt; Alemania
Fil: Caspar, Birgit. Goethe Universitat Frankfurt; Alemania
Fil: Kudlinzki, Denis. Goethe Universitat Frankfurt; Alemania. German Cancer Research Center; Alemania
Fil: Saxena, Krishna. Goethe Universitat Frankfurt; Alemania
Fil: Sreeramulu, Sridhar. Goethe Universitat Frankfurt; Alemania
Fil: Schwalbe, Harald. Goethe Universitat Frankfurt; Alemania. German Cancer Research Center; Alemania
Fil: Strebhardt, Klaus. Goethe Universitat Frankfurt; Alemania. German Cancer Research Center; Alemania
Fil: Biondi, Ricardo Miguel. German Cancer Research Center; Alemania. Goethe Universitat Frankfurt; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina
Materia
Protein kinase regulation
PLK1
small compounds
allosteric inhibition
protein-protein interaction
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/88741
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/88741
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Modulation of the Allosteric Communication between the Polo-Box Domain and the Catalytic Domain in Plk1 by Small CompoundsRaab, MonikaSanhaji, MouradPietsch, LarissaBéquignon, IsabelleHerbrand, Amanda K.Süß, EvelynGande, Santosh L.Caspar, BirgitKudlinzki, DenisSaxena, KrishnaSreeramulu, SridharSchwalbe, HaraldStrebhardt, KlausBiondi, Ricardo MiguelProtein kinase regulationPLK1small compoundsallosteric inhibitionprotein-protein interactionhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The Polo-like kinases (Plks) are an evolutionary conserved family of Ser/Thr protein kinases that possess, in addition to the classical kinase domain at the N-terminus, a C-terminal polo-box domain (PBD) that binds to phosphorylated proteins and modulates the kinase activity and its localization. Plk1, which regulates the formation of the mitotic spindle, has emerged as a validated drug target for the treatment of cancer, because it is required for numerous types of cancer cells but not for the cell division in noncancer cells. Here, we employed chemical biology methods to investigate the allosteric communication between the PBD and the catalytic domain of Plk1. We identified small compounds that bind to the catalytic domain and inhibit or enhance the interaction of Plk1 with the phosphorylated peptide PoloBoxtide in vitro. In cells, two new allosteric Plk1 inhibitors affected the proliferation of cancer cells in culture and the cell cycle but had distinct phenotypic effects on spindle formation. Both compounds inhibited Plk1 signaling, indicating that they specifically act on Plk1 in cultured cells.Fil: Raab, Monika. Goethe Universitat Frankfurt; AlemaniaFil: Sanhaji, Mourad. Goethe Universitat Frankfurt; AlemaniaFil: Pietsch, Larissa. German Cancer Research Center; Alemania. Goethe Universitat Frankfurt; AlemaniaFil: Béquignon, Isabelle. Goethe Universitat Frankfurt; AlemaniaFil: Herbrand, Amanda K.. Goethe Universitat Frankfurt; AlemaniaFil: Süß, Evelyn. Goethe Universitat Frankfurt; AlemaniaFil: Gande, Santosh L.. German Cancer Research Center; Alemania. Goethe Universitat Frankfurt; AlemaniaFil: Caspar, Birgit. Goethe Universitat Frankfurt; AlemaniaFil: Kudlinzki, Denis. Goethe Universitat Frankfurt; Alemania. German Cancer Research Center; AlemaniaFil: Saxena, Krishna. Goethe Universitat Frankfurt; AlemaniaFil: Sreeramulu, Sridhar. Goethe Universitat Frankfurt; AlemaniaFil: Schwalbe, Harald. Goethe Universitat Frankfurt; Alemania. German Cancer Research Center; AlemaniaFil: Strebhardt, Klaus. Goethe Universitat Frankfurt; Alemania. German Cancer Research Center; AlemaniaFil: Biondi, Ricardo Miguel. German Cancer Research Center; Alemania. Goethe Universitat Frankfurt; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaAmerican Chemical Society2018-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/88741Raab, Monika; Sanhaji, Mourad; Pietsch, Larissa; Béquignon, Isabelle; Herbrand, Amanda K.; et al.; Modulation of the Allosteric Communication between the Polo-Box Domain and the Catalytic Domain in Plk1 by Small Compounds; American Chemical Society; ACS Chemical Biology; 13; 8; 8-2018; 1921-19311554-8929CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1021/acschembio.7b01078info:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/acschembio.7b01078info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:09:40Zoai:ri.conicet.gov.ar:11336/88741instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 10:09:40.287CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Modulation of the Allosteric Communication between the Polo-Box Domain and the Catalytic Domain in Plk1 by Small Compounds
title Modulation of the Allosteric Communication between the Polo-Box Domain and the Catalytic Domain in Plk1 by Small Compounds
spellingShingle Modulation of the Allosteric Communication between the Polo-Box Domain and the Catalytic Domain in Plk1 by Small Compounds
Raab, Monika
Protein kinase regulation
PLK1
small compounds
allosteric inhibition
protein-protein interaction
title_short Modulation of the Allosteric Communication between the Polo-Box Domain and the Catalytic Domain in Plk1 by Small Compounds
title_full Modulation of the Allosteric Communication between the Polo-Box Domain and the Catalytic Domain in Plk1 by Small Compounds
title_fullStr Modulation of the Allosteric Communication between the Polo-Box Domain and the Catalytic Domain in Plk1 by Small Compounds
title_full_unstemmed Modulation of the Allosteric Communication between the Polo-Box Domain and the Catalytic Domain in Plk1 by Small Compounds
title_sort Modulation of the Allosteric Communication between the Polo-Box Domain and the Catalytic Domain in Plk1 by Small Compounds
dc.creator.none.fl_str_mv Raab, Monika
Sanhaji, Mourad
Pietsch, Larissa
Béquignon, Isabelle
Herbrand, Amanda K.
Süß, Evelyn
Gande, Santosh L.
Caspar, Birgit
Kudlinzki, Denis
Saxena, Krishna
Sreeramulu, Sridhar
Schwalbe, Harald
Strebhardt, Klaus
Biondi, Ricardo Miguel
author Raab, Monika
author_facet Raab, Monika
Sanhaji, Mourad
Pietsch, Larissa
Béquignon, Isabelle
Herbrand, Amanda K.
Süß, Evelyn
Gande, Santosh L.
Caspar, Birgit
Kudlinzki, Denis
Saxena, Krishna
Sreeramulu, Sridhar
Schwalbe, Harald
Strebhardt, Klaus
Biondi, Ricardo Miguel
author_role author
author2 Sanhaji, Mourad
Pietsch, Larissa
Béquignon, Isabelle
Herbrand, Amanda K.
Süß, Evelyn
Gande, Santosh L.
Caspar, Birgit
Kudlinzki, Denis
Saxena, Krishna
Sreeramulu, Sridhar
Schwalbe, Harald
Strebhardt, Klaus
Biondi, Ricardo Miguel
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Protein kinase regulation
PLK1
small compounds
allosteric inhibition
protein-protein interaction
topic Protein kinase regulation
PLK1
small compounds
allosteric inhibition
protein-protein interaction
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The Polo-like kinases (Plks) are an evolutionary conserved family of Ser/Thr protein kinases that possess, in addition to the classical kinase domain at the N-terminus, a C-terminal polo-box domain (PBD) that binds to phosphorylated proteins and modulates the kinase activity and its localization. Plk1, which regulates the formation of the mitotic spindle, has emerged as a validated drug target for the treatment of cancer, because it is required for numerous types of cancer cells but not for the cell division in noncancer cells. Here, we employed chemical biology methods to investigate the allosteric communication between the PBD and the catalytic domain of Plk1. We identified small compounds that bind to the catalytic domain and inhibit or enhance the interaction of Plk1 with the phosphorylated peptide PoloBoxtide in vitro. In cells, two new allosteric Plk1 inhibitors affected the proliferation of cancer cells in culture and the cell cycle but had distinct phenotypic effects on spindle formation. Both compounds inhibited Plk1 signaling, indicating that they specifically act on Plk1 in cultured cells.
Fil: Raab, Monika. Goethe Universitat Frankfurt; Alemania
Fil: Sanhaji, Mourad. Goethe Universitat Frankfurt; Alemania
Fil: Pietsch, Larissa. German Cancer Research Center; Alemania. Goethe Universitat Frankfurt; Alemania
Fil: Béquignon, Isabelle. Goethe Universitat Frankfurt; Alemania
Fil: Herbrand, Amanda K.. Goethe Universitat Frankfurt; Alemania
Fil: Süß, Evelyn. Goethe Universitat Frankfurt; Alemania
Fil: Gande, Santosh L.. German Cancer Research Center; Alemania. Goethe Universitat Frankfurt; Alemania
Fil: Caspar, Birgit. Goethe Universitat Frankfurt; Alemania
Fil: Kudlinzki, Denis. Goethe Universitat Frankfurt; Alemania. German Cancer Research Center; Alemania
Fil: Saxena, Krishna. Goethe Universitat Frankfurt; Alemania
Fil: Sreeramulu, Sridhar. Goethe Universitat Frankfurt; Alemania
Fil: Schwalbe, Harald. Goethe Universitat Frankfurt; Alemania. German Cancer Research Center; Alemania
Fil: Strebhardt, Klaus. Goethe Universitat Frankfurt; Alemania. German Cancer Research Center; Alemania
Fil: Biondi, Ricardo Miguel. German Cancer Research Center; Alemania. Goethe Universitat Frankfurt; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina
description The Polo-like kinases (Plks) are an evolutionary conserved family of Ser/Thr protein kinases that possess, in addition to the classical kinase domain at the N-terminus, a C-terminal polo-box domain (PBD) that binds to phosphorylated proteins and modulates the kinase activity and its localization. Plk1, which regulates the formation of the mitotic spindle, has emerged as a validated drug target for the treatment of cancer, because it is required for numerous types of cancer cells but not for the cell division in noncancer cells. Here, we employed chemical biology methods to investigate the allosteric communication between the PBD and the catalytic domain of Plk1. We identified small compounds that bind to the catalytic domain and inhibit or enhance the interaction of Plk1 with the phosphorylated peptide PoloBoxtide in vitro. In cells, two new allosteric Plk1 inhibitors affected the proliferation of cancer cells in culture and the cell cycle but had distinct phenotypic effects on spindle formation. Both compounds inhibited Plk1 signaling, indicating that they specifically act on Plk1 in cultured cells.
publishDate 2018
dc.date.none.fl_str_mv 2018-08
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/88741
Raab, Monika; Sanhaji, Mourad; Pietsch, Larissa; Béquignon, Isabelle; Herbrand, Amanda K.; et al.; Modulation of the Allosteric Communication between the Polo-Box Domain and the Catalytic Domain in Plk1 by Small Compounds; American Chemical Society; ACS Chemical Biology; 13; 8; 8-2018; 1921-1931
1554-8929
CONICET Digital
CONICET
url http://hdl.handle.net/11336/88741
identifier_str_mv Raab, Monika; Sanhaji, Mourad; Pietsch, Larissa; Béquignon, Isabelle; Herbrand, Amanda K.; et al.; Modulation of the Allosteric Communication between the Polo-Box Domain and the Catalytic Domain in Plk1 by Small Compounds; American Chemical Society; ACS Chemical Biology; 13; 8; 8-2018; 1921-1931
1554-8929
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1021/acschembio.7b01078
info:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/acschembio.7b01078
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Chemical Society
publisher.none.fl_str_mv American Chemical Society
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1842270090374938624
score 13.13397

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