Mapping the Interface of a GPCR Dimer : A Structural Model of the A Adenosine and D Dopamine Receptor Heteromer
Borroto-Escuela, Dasiel O. (Karolinska Institutet (Estocolm, Suècia)
Rodriguez, David (Science for Life Laboratory, Stockholm University)
Romero-Fernandez, Wilber (Uppsala University)
Kapla, Jon (Uppsala University)
Jaiteh, Mariama (Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University)
Ranganathan, Anirudh (Stockholm University)
Lazarova, Tzvetana (Universitat Autònoma de Barcelona. Institut de Neurociències)
Fuxe, Kjell (Karolinska Institutet (Estocolm, Suècia))
Carlsson, Jens (Uppsala University)

Data:	2018
Resum:	The A adenosine (AR) and D dopamine (DR) receptors form oligomers in the cell membrane and allosteric interactions across the AR-DR heteromer represent a target for development of drugs against central nervous system disorders. However, understanding of the molecular determinants of AR-DR heteromerization and the allosteric antagonistic interactions between the receptor protomers is still limited. In this work, a structural model of the AR-DR 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 AR-DR receptor-receptor interactions in bioluminescence resonance energy transfer (BRET) and proximity ligation assays. Peptides corresponding to TM-IV and TM-V of the AR blocked heterodimer interactions and disrupted the allosteric effect of AR activation on DR agonist binding. Protein-protein docking was used to construct a model of the AR-DR heterodimer with a TM-IV/V interface, which was refined using molecular dynamics simulations. Mutations in the predicted interface reduced AR-DR 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 AR-DR interface can be extended to study the many other G protein-coupled receptors that engage in heteroreceptor complexes.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	G protein-coupled receptor ; D dopamine receptor ; A adenosine receptor ; Heteroreceptor complex ; Dimerization ; Dimer interface ; Allosteric modulation
Publicat a:	Frontiers in Pharmacology, Vol. 9 (august 2018) , ISSN 1663-9812

DOI: 10.3389/fphar.2018.00829
PMID: 30214407

16 p, 4.5 MB

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