Experimental and computational analysis of biased agonism on full-length and a C-terminally truncated adenosine A2A receptor

Biased agonism, the ability of agonists to differentially activate downstream signaling pathways by stabilizing specific receptor conformations, is a key issue for G protein-coupled receptor (GPCR) signaling. The C-terminal domain might influence this functional selectivity of GPCRs as it engages G...

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Autores: Navarro Brugal, Gemma, González, Ángel, Campanacci, Stefano, Rivas‐Santisteban, Rafael, Reyes Resina, Irene, Casajuana-Martin, Nil, Cordomí, Arnau, Pardo, Leonardo, Franco Fernández, Rafael
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/177847
Acesso em linha:https://hdl.handle.net/2445/177847
Access Level:acceso abierto
Palavra-chave:Proteïnes G
Adenosina
Dinàmica molecular
G Proteins
Adenosine
Molecular dynamics
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spelling Experimental and computational analysis of biased agonism on full-length and a C-terminally truncated adenosine A2A receptorNavarro Brugal, GemmaGonzález, ÁngelCampanacci, StefanoRivas‐Santisteban, RafaelReyes Resina, IreneCasajuana-Martin, NilCordomí, ArnauPardo, LeonardoFranco Fernández, RafaelProteïnes GAdenosinaDinàmica molecularG ProteinsAdenosineMolecular dynamicsBiased agonism, the ability of agonists to differentially activate downstream signaling pathways by stabilizing specific receptor conformations, is a key issue for G protein-coupled receptor (GPCR) signaling. The C-terminal domain might influence this functional selectivity of GPCRs as it engages G proteins, GPCR kinases, β-arrestins, and several other proteins. Thus, the aim of this paper is to compare the agonist-dependent selectivity for intracellular pathways in a heterologous system expressing the full-length (A2AR) and a C-tail truncated (A2AΔ40R lacking the last 40 amino acids) adenosine A2A receptor, a GPCR that is already targeted in Parkinson's disease using a first-in-class drug. Experimental data such as ligand binding, cAMP production, β-arrestin recruitment, ERK1/2 phosphorylation and dynamic mass redistribution assays, which correspond to different aspects of signal transduction, were measured upon the action of structurally diverse compounds (the agonists adenosine, NECA, CGS-21680, PSB-0777 and LUF-5834 and the SCH-58261 antagonist) in cells expressing A2AR and A2AΔ40R. The results show that taking cAMP levels and the endogenous adenosine agonist as references, the main difference in bias was obtained with PSB-0777 and LUF-5834. The C-terminus is dispensable for both G-protein and β-arrestin recruitment and also for MAPK activation. Unrestrained molecular dynamics simulations, at the μs timescale, were used to understand the structural arrangements of the binding cavity, triggered by these chemically different agonists, facilitating G protein binding with different efficacy.Research Network of Computational and Structural Biotechnology (RNCSB)2021202120202021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion10 p.application/pdfapplication/pdfhttps://hdl.handle.net/2445/177847Articles publicats en revistes (Bioquímica i Biomedicina Molecular)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1016/j.csbj.2020.09.028Computational and Structural Biotechnology Journal, 2020, vol. 18, p. 2723-2732https://doi.org/10.1016/j.csbj.2020.09.028cc-by-nc-nd (c) Navarro Brugal, Gemma et al., 2020https://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1778472026-05-29T05:05:01Z
dc.title.none.fl_str_mv Experimental and computational analysis of biased agonism on full-length and a C-terminally truncated adenosine A2A receptor
title Experimental and computational analysis of biased agonism on full-length and a C-terminally truncated adenosine A2A receptor
spellingShingle Experimental and computational analysis of biased agonism on full-length and a C-terminally truncated adenosine A2A receptor
Navarro Brugal, Gemma
Proteïnes G
Adenosina
Dinàmica molecular
G Proteins
Adenosine
Molecular dynamics
title_short Experimental and computational analysis of biased agonism on full-length and a C-terminally truncated adenosine A2A receptor
title_full Experimental and computational analysis of biased agonism on full-length and a C-terminally truncated adenosine A2A receptor
title_fullStr Experimental and computational analysis of biased agonism on full-length and a C-terminally truncated adenosine A2A receptor
title_full_unstemmed Experimental and computational analysis of biased agonism on full-length and a C-terminally truncated adenosine A2A receptor
title_sort Experimental and computational analysis of biased agonism on full-length and a C-terminally truncated adenosine A2A receptor
dc.creator.none.fl_str_mv Navarro Brugal, Gemma
González, Ángel
Campanacci, Stefano
Rivas‐Santisteban, Rafael
Reyes Resina, Irene
Casajuana-Martin, Nil
Cordomí, Arnau
Pardo, Leonardo
Franco Fernández, Rafael
author Navarro Brugal, Gemma
author_facet Navarro Brugal, Gemma
González, Ángel
Campanacci, Stefano
Rivas‐Santisteban, Rafael
Reyes Resina, Irene
Casajuana-Martin, Nil
Cordomí, Arnau
Pardo, Leonardo
Franco Fernández, Rafael
author_role author
author2 González, Ángel
Campanacci, Stefano
Rivas‐Santisteban, Rafael
Reyes Resina, Irene
Casajuana-Martin, Nil
Cordomí, Arnau
Pardo, Leonardo
Franco Fernández, Rafael
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Proteïnes G
Adenosina
Dinàmica molecular
G Proteins
Adenosine
Molecular dynamics
topic Proteïnes G
Adenosina
Dinàmica molecular
G Proteins
Adenosine
Molecular dynamics
description Biased agonism, the ability of agonists to differentially activate downstream signaling pathways by stabilizing specific receptor conformations, is a key issue for G protein-coupled receptor (GPCR) signaling. The C-terminal domain might influence this functional selectivity of GPCRs as it engages G proteins, GPCR kinases, β-arrestins, and several other proteins. Thus, the aim of this paper is to compare the agonist-dependent selectivity for intracellular pathways in a heterologous system expressing the full-length (A2AR) and a C-tail truncated (A2AΔ40R lacking the last 40 amino acids) adenosine A2A receptor, a GPCR that is already targeted in Parkinson's disease using a first-in-class drug. Experimental data such as ligand binding, cAMP production, β-arrestin recruitment, ERK1/2 phosphorylation and dynamic mass redistribution assays, which correspond to different aspects of signal transduction, were measured upon the action of structurally diverse compounds (the agonists adenosine, NECA, CGS-21680, PSB-0777 and LUF-5834 and the SCH-58261 antagonist) in cells expressing A2AR and A2AΔ40R. The results show that taking cAMP levels and the endogenous adenosine agonist as references, the main difference in bias was obtained with PSB-0777 and LUF-5834. The C-terminus is dispensable for both G-protein and β-arrestin recruitment and also for MAPK activation. Unrestrained molecular dynamics simulations, at the μs timescale, were used to understand the structural arrangements of the binding cavity, triggered by these chemically different agonists, facilitating G protein binding with different efficacy.
publishDate 2020
dc.date.none.fl_str_mv 2020
2021
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/177847
url https://hdl.handle.net/2445/177847
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1016/j.csbj.2020.09.028
Computational and Structural Biotechnology Journal, 2020, vol. 18, p. 2723-2732
https://doi.org/10.1016/j.csbj.2020.09.028
dc.rights.none.fl_str_mv cc-by-nc-nd (c) Navarro Brugal, Gemma et al., 2020
https://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by-nc-nd (c) Navarro Brugal, Gemma et al., 2020
https://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 10 p.
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Research Network of Computational and Structural Biotechnology (RNCSB)
publisher.none.fl_str_mv Research Network of Computational and Structural Biotechnology (RNCSB)
dc.source.none.fl_str_mv Articles publicats en revistes (Bioquímica i Biomedicina Molecular)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,81155

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