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Mapping the Interface of a GPCR Dimer: A Structural Model of the A2A Adenosine and D2 Dopamine Receptor Heteromer.


ABSTRACT: 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.

SUBMITTER: Borroto-Escuela DO 

PROVIDER: S-EPMC6125358 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Mapping the Interface of a GPCR Dimer: A Structural Model of the A<sub>2A</sub> Adenosine and D<sub>2</sub> Dopamine Receptor Heteromer.

Borroto-Escuela Dasiel O DO   Rodriguez David D   Romero-Fernandez Wilber W   Kapla Jon J   Jaiteh Mariama M   Ranganathan Anirudh A   Lazarova Tzvetana T   Fuxe Kjell K   Carlsson Jens J  

Frontiers in pharmacology 20180830


The A<sub>2A</sub> adenosine (A<sub>2A</sub>R) and D<sub>2</sub> dopamine (D<sub>2</sub>R) receptors form oligomers in the cell membrane and allosteric interactions across the A<sub>2A</sub>R-D<sub>2</sub>R heteromer represent a target for development of drugs against central nervous system disorders. However, understanding of the molecular determinants of A<sub>2A</sub>R-D<sub>2</sub>R heteromerization and the allosteric antagonistic interactions between the receptor protomers is still limited.  ...[more]

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