Bidirectional Allosteric Communication between the ATP-Binding Site and the Regulatory PIF Pocket in PDK1 Protein Kinase

Autores
Schulze, Jörg O.; Saladino, Giorgio; Busschots, Katrien; Neimanis, Sonja; Süß, Evelyn; Odadzic, Dalibor; Zeuzem, Stefan; Hindie, Valerie; Herbrand, Amanda K.; Lisa, María Natalia; Alzari, Pedro M.; Gervasio, Francesco L.; Biondi, Ricardo Miguel
Año de publicación
2016
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Allostery is a phenomenon observed in many proteins where binding of a macromolecular partner or a small-molecule ligand at one location leads to specific perturbations at a site not in direct contact with the region where the binding occurs. The list of proteins under allosteric regulation includes AGC protein kinases. AGC kinases have a conserved allosteric site, the phosphoinositide-dependent protein kinase 1 (PDK1)-interacting fragment (PIF) pocket, which regulates protein ATP-binding, activity, and interaction with substrates. In this study, we identify small molecules that bind to the ATP-binding site and affect the PIF pocket of AGC kinase family members, PDK1 and Aurora kinase. We describe the mechanistic details and show that although PDK1 and Aurora kinase inhibitors bind to the conserved ATP-binding site, they differentially modulate physiological interactions at the PIF-pocket site. Our work outlines a strategy for developing bidirectional small-molecule allosteric modulators of protein kinases and other signaling proteins.
Fil: Schulze, Jörg O.. Goethe Universitat Frankfurt; Alemania
Fil: Saladino, Giorgio. University College London; Reino Unido
Fil: Busschots, Katrien. Goethe Universitat Frankfurt; Alemania
Fil: Neimanis, Sonja. Goethe Universitat Frankfurt; Alemania
Fil: Süß, Evelyn. Goethe Universitat Frankfurt; Alemania
Fil: Odadzic, Dalibor. Goethe Universitat Frankfurt; Alemania
Fil: Zeuzem, Stefan. Goethe Universitat Frankfurt; Alemania
Fil: Hindie, Valerie. Goethe Universitat Frankfurt; Alemania
Fil: Herbrand, Amanda K.. Goethe Universitat Frankfurt; Alemania
Fil: Lisa, María Natalia. Instituto Pasteur; Francia. Instituto Pasteur de Montevideo; Uruguay. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Alzari, Pedro M.. Instituto Pasteur; Francia
Fil: Gervasio, Francesco L.. University College London; Reino Unido
Fil: Biondi, Ricardo Miguel. 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. Goethe Universitat Frankfurt; Alemania. German Cancer Research Center; Alemania
Materia
Adenosine
Agc Kinase
Allosteric Regulation
Aurora
Gsk2334470
Molecular Dynamics
Pdk1
Pif Pocket
Protein Kinase
Small Compounds
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:11336/55476
Acceder
id CONICETDig_6dcb8666ee2dbd50d8832bafbb309fe9
oai_identifier_str oai:ri.conicet.gov.ar:11336/55476
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Bidirectional Allosteric Communication between the ATP-Binding Site and the Regulatory PIF Pocket in PDK1 Protein KinaseSchulze, Jörg O.Saladino, GiorgioBusschots, KatrienNeimanis, SonjaSüß, EvelynOdadzic, DaliborZeuzem, StefanHindie, ValerieHerbrand, Amanda K.Lisa, María NataliaAlzari, Pedro M.Gervasio, Francesco L.Biondi, Ricardo MiguelAdenosineAgc KinaseAllosteric RegulationAuroraGsk2334470Molecular DynamicsPdk1Pif PocketProtein KinaseSmall Compoundshttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Allostery is a phenomenon observed in many proteins where binding of a macromolecular partner or a small-molecule ligand at one location leads to specific perturbations at a site not in direct contact with the region where the binding occurs. The list of proteins under allosteric regulation includes AGC protein kinases. AGC kinases have a conserved allosteric site, the phosphoinositide-dependent protein kinase 1 (PDK1)-interacting fragment (PIF) pocket, which regulates protein ATP-binding, activity, and interaction with substrates. In this study, we identify small molecules that bind to the ATP-binding site and affect the PIF pocket of AGC kinase family members, PDK1 and Aurora kinase. We describe the mechanistic details and show that although PDK1 and Aurora kinase inhibitors bind to the conserved ATP-binding site, they differentially modulate physiological interactions at the PIF-pocket site. Our work outlines a strategy for developing bidirectional small-molecule allosteric modulators of protein kinases and other signaling proteins.Fil: Schulze, Jörg O.. Goethe Universitat Frankfurt; AlemaniaFil: Saladino, Giorgio. University College London; Reino UnidoFil: Busschots, Katrien. Goethe Universitat Frankfurt; AlemaniaFil: Neimanis, Sonja. Goethe Universitat Frankfurt; AlemaniaFil: Süß, Evelyn. Goethe Universitat Frankfurt; AlemaniaFil: Odadzic, Dalibor. Goethe Universitat Frankfurt; AlemaniaFil: Zeuzem, Stefan. Goethe Universitat Frankfurt; AlemaniaFil: Hindie, Valerie. Goethe Universitat Frankfurt; AlemaniaFil: Herbrand, Amanda K.. Goethe Universitat Frankfurt; AlemaniaFil: Lisa, María Natalia. Instituto Pasteur; Francia. Instituto Pasteur de Montevideo; Uruguay. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Alzari, Pedro M.. Instituto Pasteur; FranciaFil: Gervasio, Francesco L.. University College London; Reino UnidoFil: Biondi, Ricardo Miguel. 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. Goethe Universitat Frankfurt; Alemania. German Cancer Research Center; AlemaniaCell Press2016-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/55476Schulze, Jörg O.; Saladino, Giorgio; Busschots, Katrien; Neimanis, Sonja; Süß, Evelyn; et al.; Bidirectional Allosteric Communication between the ATP-Binding Site and the Regulatory PIF Pocket in PDK1 Protein Kinase; Cell Press; Cell Chemical Biology; 23; 10; 10-2016; 1193-12052451-94562451-9448CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.chembiol.2016.06.017info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S2451945616303026info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:43:30Zoai:ri.conicet.gov.ar:11336/55476instacron: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 09:43:31.252CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Bidirectional Allosteric Communication between the ATP-Binding Site and the Regulatory PIF Pocket in PDK1 Protein Kinase
title Bidirectional Allosteric Communication between the ATP-Binding Site and the Regulatory PIF Pocket in PDK1 Protein Kinase
spellingShingle Bidirectional Allosteric Communication between the ATP-Binding Site and the Regulatory PIF Pocket in PDK1 Protein Kinase
Schulze, Jörg O.
Adenosine
Agc Kinase
Allosteric Regulation
Aurora
Gsk2334470
Molecular Dynamics
Pdk1
Pif Pocket
Protein Kinase
Small Compounds
title_short Bidirectional Allosteric Communication between the ATP-Binding Site and the Regulatory PIF Pocket in PDK1 Protein Kinase
title_full Bidirectional Allosteric Communication between the ATP-Binding Site and the Regulatory PIF Pocket in PDK1 Protein Kinase
title_fullStr Bidirectional Allosteric Communication between the ATP-Binding Site and the Regulatory PIF Pocket in PDK1 Protein Kinase
title_full_unstemmed Bidirectional Allosteric Communication between the ATP-Binding Site and the Regulatory PIF Pocket in PDK1 Protein Kinase
title_sort Bidirectional Allosteric Communication between the ATP-Binding Site and the Regulatory PIF Pocket in PDK1 Protein Kinase
dc.creator.none.fl_str_mv Schulze, Jörg O.
Saladino, Giorgio
Busschots, Katrien
Neimanis, Sonja
Süß, Evelyn
Odadzic, Dalibor
Zeuzem, Stefan
Hindie, Valerie
Herbrand, Amanda K.
Lisa, María Natalia
Alzari, Pedro M.
Gervasio, Francesco L.
Biondi, Ricardo Miguel
author Schulze, Jörg O.
author_facet Schulze, Jörg O.
Saladino, Giorgio
Busschots, Katrien
Neimanis, Sonja
Süß, Evelyn
Odadzic, Dalibor
Zeuzem, Stefan
Hindie, Valerie
Herbrand, Amanda K.
Lisa, María Natalia
Alzari, Pedro M.
Gervasio, Francesco L.
Biondi, Ricardo Miguel
author_role author
author2 Saladino, Giorgio
Busschots, Katrien
Neimanis, Sonja
Süß, Evelyn
Odadzic, Dalibor
Zeuzem, Stefan
Hindie, Valerie
Herbrand, Amanda K.
Lisa, María Natalia
Alzari, Pedro M.
Gervasio, Francesco L.
Biondi, Ricardo Miguel
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Adenosine
Agc Kinase
Allosteric Regulation
Aurora
Gsk2334470
Molecular Dynamics
Pdk1
Pif Pocket
Protein Kinase
Small Compounds
topic Adenosine
Agc Kinase
Allosteric Regulation
Aurora
Gsk2334470
Molecular Dynamics
Pdk1
Pif Pocket
Protein Kinase
Small Compounds
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Allostery is a phenomenon observed in many proteins where binding of a macromolecular partner or a small-molecule ligand at one location leads to specific perturbations at a site not in direct contact with the region where the binding occurs. The list of proteins under allosteric regulation includes AGC protein kinases. AGC kinases have a conserved allosteric site, the phosphoinositide-dependent protein kinase 1 (PDK1)-interacting fragment (PIF) pocket, which regulates protein ATP-binding, activity, and interaction with substrates. In this study, we identify small molecules that bind to the ATP-binding site and affect the PIF pocket of AGC kinase family members, PDK1 and Aurora kinase. We describe the mechanistic details and show that although PDK1 and Aurora kinase inhibitors bind to the conserved ATP-binding site, they differentially modulate physiological interactions at the PIF-pocket site. Our work outlines a strategy for developing bidirectional small-molecule allosteric modulators of protein kinases and other signaling proteins.
Fil: Schulze, Jörg O.. Goethe Universitat Frankfurt; Alemania
Fil: Saladino, Giorgio. University College London; Reino Unido
Fil: Busschots, Katrien. Goethe Universitat Frankfurt; Alemania
Fil: Neimanis, Sonja. Goethe Universitat Frankfurt; Alemania
Fil: Süß, Evelyn. Goethe Universitat Frankfurt; Alemania
Fil: Odadzic, Dalibor. Goethe Universitat Frankfurt; Alemania
Fil: Zeuzem, Stefan. Goethe Universitat Frankfurt; Alemania
Fil: Hindie, Valerie. Goethe Universitat Frankfurt; Alemania
Fil: Herbrand, Amanda K.. Goethe Universitat Frankfurt; Alemania
Fil: Lisa, María Natalia. Instituto Pasteur; Francia. Instituto Pasteur de Montevideo; Uruguay. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Alzari, Pedro M.. Instituto Pasteur; Francia
Fil: Gervasio, Francesco L.. University College London; Reino Unido
Fil: Biondi, Ricardo Miguel. 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. Goethe Universitat Frankfurt; Alemania. German Cancer Research Center; Alemania
description Allostery is a phenomenon observed in many proteins where binding of a macromolecular partner or a small-molecule ligand at one location leads to specific perturbations at a site not in direct contact with the region where the binding occurs. The list of proteins under allosteric regulation includes AGC protein kinases. AGC kinases have a conserved allosteric site, the phosphoinositide-dependent protein kinase 1 (PDK1)-interacting fragment (PIF) pocket, which regulates protein ATP-binding, activity, and interaction with substrates. In this study, we identify small molecules that bind to the ATP-binding site and affect the PIF pocket of AGC kinase family members, PDK1 and Aurora kinase. We describe the mechanistic details and show that although PDK1 and Aurora kinase inhibitors bind to the conserved ATP-binding site, they differentially modulate physiological interactions at the PIF-pocket site. Our work outlines a strategy for developing bidirectional small-molecule allosteric modulators of protein kinases and other signaling proteins.
publishDate 2016
dc.date.none.fl_str_mv 2016-10
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/11336/55476
Schulze, Jörg O.; Saladino, Giorgio; Busschots, Katrien; Neimanis, Sonja; Süß, Evelyn; et al.; Bidirectional Allosteric Communication between the ATP-Binding Site and the Regulatory PIF Pocket in PDK1 Protein Kinase; Cell Press; Cell Chemical Biology; 23; 10; 10-2016; 1193-1205
2451-9456
2451-9448
CONICET Digital
CONICET
url http://hdl.handle.net/11336/55476
identifier_str_mv Schulze, Jörg O.; Saladino, Giorgio; Busschots, Katrien; Neimanis, Sonja; Süß, Evelyn; et al.; Bidirectional Allosteric Communication between the ATP-Binding Site and the Regulatory PIF Pocket in PDK1 Protein Kinase; Cell Press; Cell Chemical Biology; 23; 10; 10-2016; 1193-1205
2451-9456
2451-9448
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.chembiol.2016.06.017
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S2451945616303026
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
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Cell Press
publisher.none.fl_str_mv Cell Press
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_ 1842268607515459584
score 13.13397

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