RT Journal Article
T1 Mapping the interface of a GPCR Dimer: A structural model of the A2A Adenosine and D2 dopamine receptor heteromer
A1 Borroto-Escuela, Dasiel O.
A1 Rodriguez, David
A1 Romero-Fernandez, Wilber
A1 Kapla, Jon
A1 Jaiteh, Mariama
A1 Ranganathan, Anirudh
A1 Lazarova, Tzvetana
A1 Fuxe, Kjell
A1 Carlsson, Jens
K1 Dopamina - Receptores
AB 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.
PB Frontiers
SN 16639812
YR 2018
FD 2018-08-30
LK https://hdl.handle.net/10630/45005
UL https://hdl.handle.net/10630/45005
LA eng
NO 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.
NO Swedish Medical Research Council
NO Åke Wibergs Stiftelse
NO Science for Life Laboratory (SciLifeLab)
NO Sven och Lilly Lawski Foundation
NO Hjärnfonden
NO Swedish National Infrastructure for Computing (SNIC)
DS RIUMA. Repositorio Institucional de la Universidad de Málaga
RD 27 feb 2026