Mapping the interface of a GPCR Dimer: A structural model of the A<inf>2A</inf> Adenosine and D<inf>2</inf> dopamine receptor heteromer

Dasiel O. Borroto-Escuela, David Rodriguez, Wilber Romero-Fernandez, Jon Kapla, Mariama Jaiteh, Anirudh Ranganathan, Tzvetana Lazarova, Kjell Fuxe, Jens Carlsson

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    © 2018 Borroto-Escuela, Rodriguez, Romero-Fernandez, Kapla, Jaiteh, Ranganathan, Lazarova, Fuxe and Carlsson. 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.
    Original languageEnglish
    Article number829
    JournalFrontiers in Pharmacology
    Issue numberAUG
    Publication statusPublished - 30 Aug 2018


    • A adenosine receptor 2A
    • Allosteric modulation
    • D dopamine receptor 2
    • Dimer interface
    • Dimerization
    • G protein-coupled receptor
    • Heteroreceptor complex


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