Mechanistic insight into the impact of a bivalent ligand on the structure and dynamics of a GPCR oligomer
| dc.authorid | 0000-0002-3367-7566 | |
| dc.authorid | 0000-0001-5950-3436 | |
| dc.contributor.author | Mansoor, Samman | |
| dc.contributor.author | Kayık, Gülru | |
| dc.contributor.author | Durdağı, Serdar | |
| dc.contributor.author | Şensoy, Özge | |
| dc.date.accessioned | 2022-03-22T08:12:28Z | |
| dc.date.available | 2022-03-22T08:12:28Z | |
| dc.date.issued | 2022 | |
| dc.department | İstanbul Medipol Üniversitesi, Mühendislik ve Doğa Bilimleri Fakültesi, Biyomedikal Mühendisliği Bölümü | |
| dc.department | İstanbul Medipol Üniversitesi, Rektörlük, Rejeneratif ve Restoratif Tıp Araştırmaları Merkezi (REMER) | |
| dc.department | İstanbul Medipol Üniversitesi, Rektörlük, Sağlık Bilim ve Teknolojileri Araştırma Enstitüsü | |
| dc.department | İstanbul Medipol Üniversitesi, Mühendislik ve Doğa Bilimleri Fakültesi, Bilgisayar Mühendisliği Bölümü | |
| dc.description.abstract | 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. | |
| dc.description.sponsorship | European Cooperation in Science and Technology (COST) | en_US |
| dc.identifier.citation | Mansoor, S., Kayık, G., Durdağı, S. ve Şensoy, Ö. (2022). Mechanistic insight into the impact of a bivalent ligand on the structure and dynamics of a GPCR oligomer. Computational and Structural Biotechnology Journal, 20, 925-936. https://doi.org/10.1016/j.csbj.2022.01.016 | |
| dc.identifier.doi | 10.1016/j.csbj.2022.01.016 | |
| dc.identifier.endpage | 936 | |
| dc.identifier.issn | 2001-0370 | |
| dc.identifier.pmid | 35242285 | |
| dc.identifier.scopus | 2-s2.0-85125840978 | |
| dc.identifier.scopusquality | Q1 | |
| dc.identifier.startpage | 925 | |
| dc.identifier.uri | https://doi.org/10.1016/j.csbj.2022.01.016 | |
| dc.identifier.uri | https://hdl.handle.net/20.500.12511/9153 | |
| dc.identifier.volume | 20 | |
| dc.identifier.wos | 000778344800003 | en_US |
| dc.identifier.wosquality | Q1 | |
| dc.indekslendigikaynak | Web of Science | |
| dc.indekslendigikaynak | Scopus | |
| dc.indekslendigikaynak | PubMed | |
| dc.institutionauthor | Mansoor, Samman | |
| dc.institutionauthor | Şensoy, Özge | |
| dc.language.iso | en | |
| dc.publisher | Elsevier B.V. | |
| dc.relation.ispartof | Computational and Structural Biotechnology Journal | en_US |
| dc.relation.publicationcategory | Makale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı | |
| dc.relation.tubitak | info:eu-repo/grantAgreement/TUBITAK/SOBAG/216S297 | |
| dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 International | * |
| dc.rights | info:eu-repo/semantics/openAccess | |
| dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
| dc.subject | Accelerated Molecular Dynamics | |
| dc.subject | G Protein-Coupled Receptor | |
| dc.subject | Heterobivalent Ligand | |
| dc.subject | Oligomerization | |
| dc.title | Mechanistic insight into the impact of a bivalent ligand on the structure and dynamics of a GPCR oligomer | |
| dc.type | Article |
