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Title: | The World of GPCR dimers - Mapping dopamine receptor D2 homodimers in different activation states and configuration arrangements | Authors: | Bueschbell, Beatriz Magalhães, Pedro R. Barreto, Carlos A. V. Melo, Rita Schiedel, Anke C. Machuqueiro, Miguel Moreira, Irina S. |
Keywords: | G protein-coupled receptor (GPCRs); Dopamine receptor D2; Homodimers Dimer interface; Crosstalk; Selectivity | Issue Date: | 2023 | Publisher: | Elsevier | Project: | This work was supported by the European Regional Development Fund through the COMPETE 2020–Operational Programme for Competitiveness and Internationalization and Portuguese National Funds via Fundaç˜ao para a Ciˆencia e a Tecnologia (FCT) [LA/P/0058/ 2020, PTDC/QUI-OUT/32243/2017, DSAIPA/DS/0118/2020, UIDB/ 04046/2020, UIDP/04046/2020, UIDB/04539/2020, UIDP/04539/ 2020 and CEECIND/02300/2017]. This work was produced with the support of the Laboratory for Advanced Computing at the University of Coimbra, and it was funded by FCT I.P. under the Advanced Computing Project CPCA/A2/7219/2020. B.B. and C.A.V.B. were supported by the FCT through PhD scholarships SFRH/BD/149709/2019 and SFRH/BD/ 145457/2019 | Serial title, monograph or event: | Computational and Structural Biotechnology Journal | Volume: | 21 | Abstract: | G protein-coupled receptors (GPCRs) are known to dimerize, but the molecular and structural basis of GPCR dimers is not well understood. In this study, we developed a computational framework to generate models of symmetric and asymmetric GPCR dimers using different monomer activation states and identified their most likely interfaces with molecular details. We chose the dopamine receptor D2 (D2R) homodimer as a case study because of its biological relevance and the availability of structural information. Our results showed that transmembrane domains 4 and 5 (TM4 and TM5) are mostly found at the dimer interface of the D2R dimer and that these interfaces have a subset of key residues that are mostly nonpolar from TM4 and TM5, which was in line with experimental studies. In addition, TM2 and TM3 appear to be relevant for D2R dimers. In some cases, the inactive configuration is unaffected by the partnered protomer, whereas in others, the active protomer adopts the properties of an inactive receptor. Additionally, the β-arrestin configuration displayed the properties of an active receptor in the absence of an agonist, suggesting that a switch to another meta-state during dimerization occurred. Our findings are consistent with the experimental data, and this method can be adapted to study heterodimers and potentially extended to include additional proteins such as G proteins or β-arrestins. In summary, this approach provides insight into the impact of the conformational status of partnered protomers on the overall quaternary GPCR macromolecular structure and dynamics. | URI: | https://hdl.handle.net/10316/114488 | ISSN: | 2001-0370 | DOI: | 10.1016/j.csbj.2023.08.032 | Rights: | openAccess |
Appears in Collections: | IIIUC - Artigos em Revistas Internacionais I&D CNC - Artigos em Revistas Internacionais FCTUC Ciências da Vida - Artigos em Revistas Internacionais I&D CIBB - Artigos em Revistas Internacionais |
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