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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| Format: | Article |
| Language: | English |
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Elsevier
2022-01-01
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| Series: | Computational and Structural Biotechnology Journal |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S200103702200023X |
| _version_ | 1797978273699856384 |
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| author | Samman Mansoor Gülru Kayık Serdar Durdagi Ozge Sensoy |
| author_facet | Samman Mansoor Gülru Kayık Serdar Durdagi Ozge Sensoy |
| author_sort | Samman Mansoor |
| collection | DOAJ |
| 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 (A2AR) dimer in the context of a modeled tetramer, which consists of A2AR and dopamine 2 receptor (D2R) 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 A2AR dimer was also transmitted to apo D2R, which is part of the neighboring D2R 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. |
| first_indexed | 2024-04-11T05:20:16Z |
| format | Article |
| id | doaj.art-39b8408e73004486b905e5b057884f2f |
| institution | Directory Open Access Journal |
| issn | 2001-0370 |
| language | English |
| last_indexed | 2024-04-11T05:20:16Z |
| publishDate | 2022-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Computational and Structural Biotechnology Journal |
| spelling | doaj.art-39b8408e73004486b905e5b057884f2f2022-12-24T04:51:18ZengElsevierComputational and Structural Biotechnology Journal2001-03702022-01-0120925936Mechanistic insight into the impact of a bivalent ligand on the structure and dynamics of a GPCR oligomerSamman Mansoor0Gülru Kayık1Serdar Durdagi2Ozge Sensoy3School of Engineering and Natural Sciences, Department of Biomedical Engineering and Bioinformatics, Istanbul Medipol University, Istanbul 34810, TurkeyComputational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, TurkeyComputational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, TurkeyRegenerative and Restorative Medicine Research Center (REMER), Research Institute for Health Sciencesand Technologies (SABITA), Istanbul Medipol University, 34810 Istanbul, Turkey; School of Engineering and Natural Sciences, Department of Computer Engineering, Istanbul Medipol University, Turkey; Corresponding author at: Regenerative and Restorative Medicine Research Center (REMER), Research Institute for Health Sciencesand Technologies (SABITA), Istanbul Medipol University, 34810 Istanbul, Turkey.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 (A2AR) dimer in the context of a modeled tetramer, which consists of A2AR and dopamine 2 receptor (D2R) 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 A2AR dimer was also transmitted to apo D2R, which is part of the neighboring D2R 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.http://www.sciencedirect.com/science/article/pii/S200103702200023XG protein-coupled receptorHeterobivalent ligandAccelerated molecular dynamicsOligomerization |
| spellingShingle | Samman Mansoor Gülru Kayık Serdar Durdagi Ozge Sensoy Mechanistic insight into the impact of a bivalent ligand on the structure and dynamics of a GPCR oligomer Computational and Structural Biotechnology Journal G protein-coupled receptor Heterobivalent ligand Accelerated molecular dynamics Oligomerization |
| 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 | G protein-coupled receptor Heterobivalent ligand Accelerated molecular dynamics Oligomerization |
| url | http://www.sciencedirect.com/science/article/pii/S200103702200023X |
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