Mapping the Interface of a GPCR Dimer: A Structural Model of the A 2A Adenosine and D 2 Dopamine Receptor Heteromer

• Published in: Frontiers in pharmacology 2018, Vol.9, p.829
• Main Authors: Borroto-Escuela, Dasiel O, Rodriguez, David, Romero-Fernandez, Wilber, Kapla, Jon, Jaiteh, Mariama, Ranganathan, Anirudh, Lazarova, Tzvetana, Fuxe, Kjell, Carlsson, Jens
• Format: Article
• Language: English
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2018.00829

The A adenosine (A R) and D dopamine (D R) receptors form oligomers in the cell membrane and allosteric interactions across the A R-D R heteromer represent a target for development of drugs against central nervous system disorders. However, understanding of the molecular determinants of A R-D R heteromerization and the allosteric antagonistic interactions between the receptor protomers is still limited. In this work, a structural model of the A R-D R 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 A R-D R receptor-receptor interactions in bioluminescence resonance energy transfer (BRET) and proximity ligation assays. Peptides corresponding to TM-IV and TM-V of the A R blocked heterodimer interactions and disrupted the allosteric effect of A R activation on D R agonist binding. Protein-protein docking was used to construct a model of the A R-D R heterodimer with a TM-IV/V interface, which was refined using molecular dynamics simulations. Mutations in the predicted interface reduced A R-D R 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 A R-D R interface can be extended to study the many other G protein-coupled receptors that engage in heteroreceptor complexes.