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Mapping the interface of a GPCR Dimer: A structural model of the A2A Adenosine and D2 dopamine receptor heteromer Borroto-Escuela, Dasiel O. Rodriguez, David Romero-Fernandez, Wilber Kapla, Jon Jaiteh, Mariama Ranganathan, Anirudh Lazarova, Tzvetana Fuxe, Kjell Carlsson, Jens Dopamina - Receptores The A2A adenosine (A2AR) and D2 dopamine (D2R) receptors form oligomers in the cell membrane and allosteric interactions across the A2AR-D2R heteromer represent a target for development of drugs against central nervous system disorders. However, understanding of the molecular determinants of A2AR-D2R heteromerization and the allosteric antagonistic interactions between the receptor protomers is still limited. In this work, a structural model of the A2AR-D2R heterodimer was generated using a combined experimental and computational approach. Regions involved in the heteromer interface were modeled based on the effects of peptides derived from the transmembrane (TM) helices on A2AR-D2R receptor-receptor interactions in bioluminescence resonance energy transfer (BRET) and proximity ligation assays. Peptides corresponding to TM-IV and TM-V of the A2AR blocked heterodimer interactions and disrupted the allosteric effect of A2AR activation on D2R agonist binding. Protein-protein docking was used to construct a model of the A2AR-D2R heterodimer with a TM-IV/V interface, which was refined using molecular dynamics simulations. Mutations in the predicted interface reduced A2AR-D2R interactions in BRET experiments and altered the allosteric modulation. The heterodimer model provided insights into the structural basis of allosteric modulation and the technique developed to characterize the A2AR-D2R interface can be extended to study the many other G protein-coupled receptors that engage in heteroreceptor complexes. 2018-08-30 journal article Borroto-Escuela DO, Rodriguez D, Romero-Fernandez W, Kapla J, Jaiteh M, Ranganathan A, Lazarova T, Fuxe K, Carlsson J. Mapping the Interface of a GPCR Dimer: A Structural Model of the A2A Adenosine and D2 Dopamine Receptor Heteromer. Frontiers in Pharmacology. 2018;9:829. doi:10.3389/fphar.2018.00829. ISSN:1663-9812. 16639812 https://hdl.handle.net/10630/45005 10.3389/fphar.2018.00829 eng info:eu-repo/grantAgreement/Swedish_Research_Council//2013-5708/SE/// info:eu-repo/grantAgreement/Swedish_Research_Council//2017-4676/SE/// info:eu-repo/grantAgreement/Swedish_Research_Council//04X-715/SE/// info:eu-repo/grantAgreement/Hjarnfonden//FO2016-0302/SE/// http://creativecommons.org/licenses/by/4.0/ open access Attribution 4.0 International Frontiers