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Mechanistic insight into the impact of a bivalent ligand on the structure and dynamics of a GPCR oligomer

Development of effective bivalent ligands has become the focus of intensive research toward modulation of G protein-coupled receptor (GPCR) oligomers, particularly in the field of GPCR pharmacology. Experimental studies have shown that they increased binding affinity and signaling potency compared t...

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Autores principales: Mansoor, Samman, Kayık, Gülru, Durdagi, Serdar, Sensoy, Ozge
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Research Network of Computational and Structural Biotechnology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8861583/
https://www.ncbi.nlm.nih.gov/pubmed/35242285
http://dx.doi.org/10.1016/j.csbj.2022.01.016
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author Mansoor, Samman
Kayık, Gülru
Durdagi, Serdar
Sensoy, Ozge
author_facet Mansoor, Samman
Kayık, Gülru
Durdagi, Serdar
Sensoy, Ozge
author_sort Mansoor, Samman
collection PubMed
description Development of effective bivalent ligands has become the focus of intensive research toward modulation of G protein-coupled receptor (GPCR) oligomers, particularly in the field of GPCR pharmacology. Experimental studies have shown that they increased binding affinity and signaling potency compared to their monovalent counterparts, yet underlying molecular mechanism remains elusive. To address this, we performed accelerated molecular dynamics simulations on bivalent-ligand bound Adenosine 2A receptor (A(2A)R) dimer in the context of a modeled tetramer, which consists of A(2A)R and dopamine 2 receptor (D(2)R) homodimers and their cognate G proteins. Our results demonstrate that bivalent ligand impacted interactions between pharmacophore groups and ligand binding residues, thus modulating allosteric communication network and water channel formed within the receptor. Moreover, it also strengthens contacts between receptor and G protein, by modulating the volume of ligand binding pocket and intracellular domain of the receptor. Importantly, we showed that impact evoked by the bivalent ligand on A(2A)R dimer was also transmitted to apo D(2)R, which is part of the neighboring D(2)R dimer. To the best of our knowledge, this is the first study that provides a mechanistic insight into the impact of a bivalent ligand on dynamics of a GPCR oligomer. Consequently, this will pave the way for development of effective ligands for modulation of GPCR oligomers and hence treatment of crucial diseases such as Parkinson’s disease and cancer.
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spelling pubmed-88615832022-03-02 Mechanistic insight into the impact of a bivalent ligand on the structure and dynamics of a GPCR oligomer Mansoor, Samman Kayık, Gülru Durdagi, Serdar Sensoy, Ozge Comput Struct Biotechnol J Research Article Development of effective bivalent ligands has become the focus of intensive research toward modulation of G protein-coupled receptor (GPCR) oligomers, particularly in the field of GPCR pharmacology. Experimental studies have shown that they increased binding affinity and signaling potency compared to their monovalent counterparts, yet underlying molecular mechanism remains elusive. To address this, we performed accelerated molecular dynamics simulations on bivalent-ligand bound Adenosine 2A receptor (A(2A)R) dimer in the context of a modeled tetramer, which consists of A(2A)R and dopamine 2 receptor (D(2)R) homodimers and their cognate G proteins. Our results demonstrate that bivalent ligand impacted interactions between pharmacophore groups and ligand binding residues, thus modulating allosteric communication network and water channel formed within the receptor. Moreover, it also strengthens contacts between receptor and G protein, by modulating the volume of ligand binding pocket and intracellular domain of the receptor. Importantly, we showed that impact evoked by the bivalent ligand on A(2A)R dimer was also transmitted to apo D(2)R, which is part of the neighboring D(2)R dimer. To the best of our knowledge, this is the first study that provides a mechanistic insight into the impact of a bivalent ligand on dynamics of a GPCR oligomer. Consequently, this will pave the way for development of effective ligands for modulation of GPCR oligomers and hence treatment of crucial diseases such as Parkinson’s disease and cancer. Research Network of Computational and Structural Biotechnology 2022-02-04 /pmc/articles/PMC8861583/ /pubmed/35242285 http://dx.doi.org/10.1016/j.csbj.2022.01.016 Text en © 2022 Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Article
Mansoor, Samman
Kayık, Gülru
Durdagi, Serdar
Sensoy, Ozge
Mechanistic insight into the impact of a bivalent ligand on the structure and dynamics of a GPCR oligomer
title Mechanistic insight into the impact of a bivalent ligand on the structure and dynamics of a GPCR oligomer
title_full Mechanistic insight into the impact of a bivalent ligand on the structure and dynamics of a GPCR oligomer
title_fullStr Mechanistic insight into the impact of a bivalent ligand on the structure and dynamics of a GPCR oligomer
title_full_unstemmed Mechanistic insight into the impact of a bivalent ligand on the structure and dynamics of a GPCR oligomer
title_short Mechanistic insight into the impact of a bivalent ligand on the structure and dynamics of a GPCR oligomer
title_sort mechanistic insight into the impact of a bivalent ligand on the structure and dynamics of a gpcr oligomer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8861583/
https://www.ncbi.nlm.nih.gov/pubmed/35242285
http://dx.doi.org/10.1016/j.csbj.2022.01.016
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