TY - JOUR
T1 - Mapping the interface of a GPCR Dimer: A structural model of the A2A Adenosine and D2 dopamine receptor heteromer
AU - Borroto-Escuela, Dasiel O.
AU - Rodriguez, David
AU - Romero-Fernandez, Wilber
AU - Kapla, Jon
AU - Jaiteh, Mariama
AU - Ranganathan, Anirudh
AU - Lazarova, Tzvetana
AU - Fuxe, Kjell
AU - Carlsson, Jens
PY - 2018/8/30
Y1 - 2018/8/30
N2 - © 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.
AB - © 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.
KW - A adenosine receptor 2A
KW - Allosteric modulation
KW - D dopamine receptor 2
KW - Dimer interface
KW - Dimerization
KW - G protein-coupled receptor
KW - Heteroreceptor complex
U2 - 10.3389/fphar.2018.00829
DO - 10.3389/fphar.2018.00829
M3 - Article
VL - 9
JO - Frontiers in Pharmacology
JF - Frontiers in Pharmacology
SN - 1663-9812
IS - AUG
M1 - 829
ER -