Synergistic Allostery in Multiligand-Protein Interactions

Autores
Ghode, Abhijeet; Gross, Lissy Zoe Florens; Tee, Wei Ven; Guarnera, Enrico; Berezovsky, Igor N.; Biondi, Ricardo Miguel; Anand, Ganesh S.
Año de publicación
2020
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Amide hydrogen-deuterium exchange mass spectrometry is powerful for describing combinatorial coupling effects of a cooperative ligand pair binding at noncontiguous sites: adenosine at the ATP-pocket and a docking peptide (PIFtide) at the PIF-pocket, on a model protein kinase PDK1. Binding of two ligands to PDK1 reveal multiple hotspots of synergistic allostery with cumulative effects greater than the sum of individual effects mediated by each ligand. We quantified this synergism and ranked these hotspots using a difference in deuteration-based approach, which showed that the strongest synergistic effects were observed at three of the critical catalytic loci of kinases: the αB-αC helices, and HRD-motif loop, and DFG-motif. Additionally, we observed weaker synergistic effects at a distal GHI-subdomain locus. Synergistic changes in deuterium exchange observed at a distal site but not at the intermediate sites of the large lobe of the kinase reveals allosteric propagation in proteins to operate through two modes. Direct electrostatic interactions between polar and charged amino acids that mediate targeted relay of allosteric signals, and diffused relay of allosteric signals through soft matter-like hydrophobic core amino acids. Furthermore, we provide evidence that the conserved β-3 strand lysine of protein kinases (Lys111 of PDK1) functions as an integrator node to coordinate allosteric coupling of the two ligand-binding sites. It maintains indirect interactions with the ATP-pocket and mediates a critical salt bridge with a glutamate (Glu130) of αC helix, which is conserved across all kinases. In summary, allosteric propagation in cooperative, dual-liganded enzyme targets is bidirectional and synergistic and offers a strategy for combinatorial drug development.
Fil: Ghode, Abhijeet. National University Of Singapore; Singapur
Fil: Gross, Lissy Zoe Florens. 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
Fil: Tee, Wei Ven. National University Of Singapore; Singapur
Fil: Guarnera, Enrico. Agency For Science, Technology And Research; Singapur
Fil: Berezovsky, Igor N.. Agency For Science, Technology And Research; Singapur
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
Fil: Anand, Ganesh S.. National University Of Singapore; Singapur
Materia
Protein kinase
allostery
adenosine
Hydrogen/deuterium exchange
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/143439
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/143439
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Synergistic Allostery in Multiligand-Protein InteractionsGhode, AbhijeetGross, Lissy Zoe FlorensTee, Wei VenGuarnera, EnricoBerezovsky, Igor N.Biondi, Ricardo MiguelAnand, Ganesh S.Protein kinaseallosteryadenosineHydrogen/deuterium exchangehttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Amide hydrogen-deuterium exchange mass spectrometry is powerful for describing combinatorial coupling effects of a cooperative ligand pair binding at noncontiguous sites: adenosine at the ATP-pocket and a docking peptide (PIFtide) at the PIF-pocket, on a model protein kinase PDK1. Binding of two ligands to PDK1 reveal multiple hotspots of synergistic allostery with cumulative effects greater than the sum of individual effects mediated by each ligand. We quantified this synergism and ranked these hotspots using a difference in deuteration-based approach, which showed that the strongest synergistic effects were observed at three of the critical catalytic loci of kinases: the αB-αC helices, and HRD-motif loop, and DFG-motif. Additionally, we observed weaker synergistic effects at a distal GHI-subdomain locus. Synergistic changes in deuterium exchange observed at a distal site but not at the intermediate sites of the large lobe of the kinase reveals allosteric propagation in proteins to operate through two modes. Direct electrostatic interactions between polar and charged amino acids that mediate targeted relay of allosteric signals, and diffused relay of allosteric signals through soft matter-like hydrophobic core amino acids. Furthermore, we provide evidence that the conserved β-3 strand lysine of protein kinases (Lys111 of PDK1) functions as an integrator node to coordinate allosteric coupling of the two ligand-binding sites. It maintains indirect interactions with the ATP-pocket and mediates a critical salt bridge with a glutamate (Glu130) of αC helix, which is conserved across all kinases. In summary, allosteric propagation in cooperative, dual-liganded enzyme targets is bidirectional and synergistic and offers a strategy for combinatorial drug development.Fil: Ghode, Abhijeet. National University Of Singapore; SingapurFil: Gross, Lissy Zoe Florens. 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; ArgentinaFil: Tee, Wei Ven. National University Of Singapore; SingapurFil: Guarnera, Enrico. Agency For Science, Technology And Research; SingapurFil: Berezovsky, Igor N.. Agency For Science, Technology And Research; SingapurFil: 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; ArgentinaFil: Anand, Ganesh S.. National University Of Singapore; SingapurCell Press2020-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/143439Ghode, Abhijeet; Gross, Lissy Zoe Florens; Tee, Wei Ven; Guarnera, Enrico; Berezovsky, Igor N.; et al.; Synergistic Allostery in Multiligand-Protein Interactions; Cell Press; Biophysical Journal; 119; 9; 11-2020; 1833-18480006-3495CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S000634952030730Xinfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.bpj.2020.09.019info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:10:03Zoai:ri.conicet.gov.ar:11336/143439instacron: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 10:10:04.23CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Synergistic Allostery in Multiligand-Protein Interactions
title Synergistic Allostery in Multiligand-Protein Interactions
spellingShingle Synergistic Allostery in Multiligand-Protein Interactions
Ghode, Abhijeet
Protein kinase
allostery
adenosine
Hydrogen/deuterium exchange
title_short Synergistic Allostery in Multiligand-Protein Interactions
title_full Synergistic Allostery in Multiligand-Protein Interactions
title_fullStr Synergistic Allostery in Multiligand-Protein Interactions
title_full_unstemmed Synergistic Allostery in Multiligand-Protein Interactions
title_sort Synergistic Allostery in Multiligand-Protein Interactions
dc.creator.none.fl_str_mv Ghode, Abhijeet
Gross, Lissy Zoe Florens
Tee, Wei Ven
Guarnera, Enrico
Berezovsky, Igor N.
Biondi, Ricardo Miguel
Anand, Ganesh S.
author Ghode, Abhijeet
author_facet Ghode, Abhijeet
Gross, Lissy Zoe Florens
Tee, Wei Ven
Guarnera, Enrico
Berezovsky, Igor N.
Biondi, Ricardo Miguel
Anand, Ganesh S.
author_role author
author2 Gross, Lissy Zoe Florens
Tee, Wei Ven
Guarnera, Enrico
Berezovsky, Igor N.
Biondi, Ricardo Miguel
Anand, Ganesh S.
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Protein kinase
allostery
adenosine
Hydrogen/deuterium exchange
topic Protein kinase
allostery
adenosine
Hydrogen/deuterium exchange
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Amide hydrogen-deuterium exchange mass spectrometry is powerful for describing combinatorial coupling effects of a cooperative ligand pair binding at noncontiguous sites: adenosine at the ATP-pocket and a docking peptide (PIFtide) at the PIF-pocket, on a model protein kinase PDK1. Binding of two ligands to PDK1 reveal multiple hotspots of synergistic allostery with cumulative effects greater than the sum of individual effects mediated by each ligand. We quantified this synergism and ranked these hotspots using a difference in deuteration-based approach, which showed that the strongest synergistic effects were observed at three of the critical catalytic loci of kinases: the αB-αC helices, and HRD-motif loop, and DFG-motif. Additionally, we observed weaker synergistic effects at a distal GHI-subdomain locus. Synergistic changes in deuterium exchange observed at a distal site but not at the intermediate sites of the large lobe of the kinase reveals allosteric propagation in proteins to operate through two modes. Direct electrostatic interactions between polar and charged amino acids that mediate targeted relay of allosteric signals, and diffused relay of allosteric signals through soft matter-like hydrophobic core amino acids. Furthermore, we provide evidence that the conserved β-3 strand lysine of protein kinases (Lys111 of PDK1) functions as an integrator node to coordinate allosteric coupling of the two ligand-binding sites. It maintains indirect interactions with the ATP-pocket and mediates a critical salt bridge with a glutamate (Glu130) of αC helix, which is conserved across all kinases. In summary, allosteric propagation in cooperative, dual-liganded enzyme targets is bidirectional and synergistic and offers a strategy for combinatorial drug development.
Fil: Ghode, Abhijeet. National University Of Singapore; Singapur
Fil: Gross, Lissy Zoe Florens. 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
Fil: Tee, Wei Ven. National University Of Singapore; Singapur
Fil: Guarnera, Enrico. Agency For Science, Technology And Research; Singapur
Fil: Berezovsky, Igor N.. Agency For Science, Technology And Research; Singapur
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
Fil: Anand, Ganesh S.. National University Of Singapore; Singapur
description Amide hydrogen-deuterium exchange mass spectrometry is powerful for describing combinatorial coupling effects of a cooperative ligand pair binding at noncontiguous sites: adenosine at the ATP-pocket and a docking peptide (PIFtide) at the PIF-pocket, on a model protein kinase PDK1. Binding of two ligands to PDK1 reveal multiple hotspots of synergistic allostery with cumulative effects greater than the sum of individual effects mediated by each ligand. We quantified this synergism and ranked these hotspots using a difference in deuteration-based approach, which showed that the strongest synergistic effects were observed at three of the critical catalytic loci of kinases: the αB-αC helices, and HRD-motif loop, and DFG-motif. Additionally, we observed weaker synergistic effects at a distal GHI-subdomain locus. Synergistic changes in deuterium exchange observed at a distal site but not at the intermediate sites of the large lobe of the kinase reveals allosteric propagation in proteins to operate through two modes. Direct electrostatic interactions between polar and charged amino acids that mediate targeted relay of allosteric signals, and diffused relay of allosteric signals through soft matter-like hydrophobic core amino acids. Furthermore, we provide evidence that the conserved β-3 strand lysine of protein kinases (Lys111 of PDK1) functions as an integrator node to coordinate allosteric coupling of the two ligand-binding sites. It maintains indirect interactions with the ATP-pocket and mediates a critical salt bridge with a glutamate (Glu130) of αC helix, which is conserved across all kinases. In summary, allosteric propagation in cooperative, dual-liganded enzyme targets is bidirectional and synergistic and offers a strategy for combinatorial drug development.
publishDate 2020
dc.date.none.fl_str_mv 2020-11
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/11336/143439
Ghode, Abhijeet; Gross, Lissy Zoe Florens; Tee, Wei Ven; Guarnera, Enrico; Berezovsky, Igor N.; et al.; Synergistic Allostery in Multiligand-Protein Interactions; Cell Press; Biophysical Journal; 119; 9; 11-2020; 1833-1848
0006-3495
CONICET Digital
CONICET
url http://hdl.handle.net/11336/143439
identifier_str_mv Ghode, Abhijeet; Gross, Lissy Zoe Florens; Tee, Wei Ven; Guarnera, Enrico; Berezovsky, Igor N.; et al.; Synergistic Allostery in Multiligand-Protein Interactions; Cell Press; Biophysical Journal; 119; 9; 11-2020; 1833-1848
0006-3495
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S000634952030730X
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.bpj.2020.09.019
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv 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
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score 13.13397

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