Homodimerization of CB2 cannabinoid receptor triggered by a bivalent ligand enhances cellular signaling

G protein-coupled receptors (GPCRs) exist within a landscape of interconvertible conformational states and in dynamic equilibrium between monomers and higher-order oligomers, both influenced by ligand binding. Here, we show that a homobivalent ligand formed by equal chromenopyrazole moieties as phar...

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Autores: Navarro Brugal, Gemma, Gómez-Autet, Marc, Morales, Paula, Rebassa, Joan-Biel, Llinàs del Torrent, Clàudia, Jagerovic, Nadine, Pardo, Leonardo, Franco Fernández, Rafael
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Recursos:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/218573
Acesso em linha:https://hdl.handle.net/2445/218573
Access Level:acceso abierto
Palavra-chave:Cànnabis
Lligands (Bioquímica)
Dinàmica molecular
Cannabis
Ligands (Biochemistry)
Molecular dynamics
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spelling Homodimerization of CB2 cannabinoid receptor triggered by a bivalent ligand enhances cellular signalingNavarro Brugal, GemmaGómez-Autet, MarcMorales, PaulaRebassa, Joan-BielLlinàs del Torrent, Clàudia Jagerovic, NadinePardo, LeonardoFranco Fernández, RafaelCànnabisLligands (Bioquímica)Dinàmica molecularCannabisLigands (Biochemistry)Molecular dynamicsG protein-coupled receptors (GPCRs) exist within a landscape of interconvertible conformational states and in dynamic equilibrium between monomers and higher-order oligomers, both influenced by ligand binding. Here, we show that a homobivalent ligand formed by equal chromenopyrazole moieties as pharmacophores, connected by 14 methylene units, can modulate the dynamics of the cannabinoid CB2 receptor (CB2R) homodimerization by simultaneously binding both protomers of the CB2R-CB2R homodimer. Computational and pharmacological experiments showed that one of the ligand pharmacophores binds to the orthosteric site of one protomer, and the other pharmacophore to a membrane-oriented pocket between transmembranes 1 and 7 of the partner protomer. This results in unique pharmacological properties, including increased potency in Gi-mediated signaling and enhanced recruitment of β-arrestin. Thus, by modulating dimerization dynamics, it may be possible to fine-tune CB2R activity, potentially leading to improved therapeutic outcomes.Elsevier B.V.2024info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/218573Articles publicats en revistes (Bioquímica i Biomedicina Molecular)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1016/j.phrs.2024.107363Pharmacological Research, 2024, vol. 208, p. 1-11https://doi.org/10.1016/j.phrs.2024.107363cc-by-nc-nd (c) Navarro Brugal, Gemma et al., 2024http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2185732026-05-27T06:46:51Z
dc.title.none.fl_str_mv Homodimerization of CB2 cannabinoid receptor triggered by a bivalent ligand enhances cellular signaling
title Homodimerization of CB2 cannabinoid receptor triggered by a bivalent ligand enhances cellular signaling
spellingShingle Homodimerization of CB2 cannabinoid receptor triggered by a bivalent ligand enhances cellular signaling
Navarro Brugal, Gemma
Cànnabis
Lligands (Bioquímica)
Dinàmica molecular
Cannabis
Ligands (Biochemistry)
Molecular dynamics
title_short Homodimerization of CB2 cannabinoid receptor triggered by a bivalent ligand enhances cellular signaling
title_full Homodimerization of CB2 cannabinoid receptor triggered by a bivalent ligand enhances cellular signaling
title_fullStr Homodimerization of CB2 cannabinoid receptor triggered by a bivalent ligand enhances cellular signaling
title_full_unstemmed Homodimerization of CB2 cannabinoid receptor triggered by a bivalent ligand enhances cellular signaling
title_sort Homodimerization of CB2 cannabinoid receptor triggered by a bivalent ligand enhances cellular signaling
dc.creator.none.fl_str_mv Navarro Brugal, Gemma
Gómez-Autet, Marc
Morales, Paula
Rebassa, Joan-Biel
Llinàs del Torrent, Clàudia
Jagerovic, Nadine
Pardo, Leonardo
Franco Fernández, Rafael
author Navarro Brugal, Gemma
author_facet Navarro Brugal, Gemma
Gómez-Autet, Marc
Morales, Paula
Rebassa, Joan-Biel
Llinàs del Torrent, Clàudia
Jagerovic, Nadine
Pardo, Leonardo
Franco Fernández, Rafael
author_role author
author2 Gómez-Autet, Marc
Morales, Paula
Rebassa, Joan-Biel
Llinàs del Torrent, Clàudia
Jagerovic, Nadine
Pardo, Leonardo
Franco Fernández, Rafael
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Cànnabis
Lligands (Bioquímica)
Dinàmica molecular
Cannabis
Ligands (Biochemistry)
Molecular dynamics
topic Cànnabis
Lligands (Bioquímica)
Dinàmica molecular
Cannabis
Ligands (Biochemistry)
Molecular dynamics
description G protein-coupled receptors (GPCRs) exist within a landscape of interconvertible conformational states and in dynamic equilibrium between monomers and higher-order oligomers, both influenced by ligand binding. Here, we show that a homobivalent ligand formed by equal chromenopyrazole moieties as pharmacophores, connected by 14 methylene units, can modulate the dynamics of the cannabinoid CB2 receptor (CB2R) homodimerization by simultaneously binding both protomers of the CB2R-CB2R homodimer. Computational and pharmacological experiments showed that one of the ligand pharmacophores binds to the orthosteric site of one protomer, and the other pharmacophore to a membrane-oriented pocket between transmembranes 1 and 7 of the partner protomer. This results in unique pharmacological properties, including increased potency in Gi-mediated signaling and enhanced recruitment of β-arrestin. Thus, by modulating dimerization dynamics, it may be possible to fine-tune CB2R activity, potentially leading to improved therapeutic outcomes.
publishDate 2024
dc.date.none.fl_str_mv 2024
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/2445/218573
url https://hdl.handle.net/2445/218573
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.phrs.2024.107363
Pharmacological Research, 2024, vol. 208, p. 1-11
https://doi.org/10.1016/j.phrs.2024.107363
dc.rights.none.fl_str_mv cc-by-nc-nd (c) Navarro Brugal, Gemma et al., 2024
http://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., 2024
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier B.V.
publisher.none.fl_str_mv Elsevier B.V.
dc.source.none.fl_str_mv Articles publicats en revistes (Bioquímica i Biomedicina Molecular)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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