Sökning: onr:"swepub:oai:DiVA.org:su-160063" >
Mapping the Interfa...
Mapping the Interface of a GPCR Dimer : A Structural Model of the A(2A) Adenosine and D-2 Dopamine Receptor Heteromer
-
- Borroto-Escuela, Dasiel O. (författare)
- Karolinska Institutet,Karolinska Inst, Dept Neurosci, Stockholm, Sweden
-
- Rodriguez, David (författare)
- Stockholms universitet,Institutionen för biokemi och biofysik,Science for Life Laboratory (SciLifeLab),Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden
-
- Romero Fernandez, Wilber (författare)
- Uppsala universitet,Beräkningsbiologi och bioinformatik,Science for Life Laboratory, SciLifeLab
-
visa fler...
-
- Kapla, Jon (författare)
- Uppsala universitet,Beräkningsbiologi och bioinformatik,Science for Life Laboratory, SciLifeLab
-
- Jaiteh, Mariama (författare)
- Uppsala universitet,Beräkningsbiologi och bioinformatik,Science for Life Laboratory, SciLifeLab
-
- Ranganathan, Anirudh (författare)
- Stockholms universitet,Institutionen för biokemi och biofysik,Science for Life Laboratory (SciLifeLab),Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden
-
- Lazarova, Tzvetana (författare)
- Autonomous Univ Barcelona, Fac Med, Dept Biochem & Mol Biol, Inst Neurosci, Barcelona, Spain
-
- Fuxe, Kjell (författare)
- Karolinska Institutet,Karolinska Inst, Dept Neurosci, Stockholm, Sweden
-
- Carlsson, Jens (författare)
- Uppsala universitet,Beräkningsbiologi och bioinformatik,Science for Life Laboratory, SciLifeLab
-
visa färre...
-
(creator_code:org_t)
- 2018-08-30
- 2018
- Engelska.
-
Ingår i: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 9
- Relaterad länk:
-
https://doi.org/10.3...
-
visa fler...
-
https://doi.org/10.3...
-
https://uu.diva-port... (primary) (Raw object)
-
https://urn.kb.se/re...
-
https://doi.org/10.3...
-
http://kipublication...
-
https://urn.kb.se/re...
-
visa färre...
Abstract
Ämnesord
Stäng
- The A(2A) adenosine (A(2A)R) and D-2 dopamine (D2R) receptors form oligomers in the cell membrane and allosteric interactions across the A(2A)R-D2R heteromer represent a target for development of drugs against central nervous system disorders. However, understanding of the molecular determinants of A(2A)R-D2R heteromerization and the allosteric antagonistic interactions between the receptor protomers is still limited. In this work, a structural model of the A(2A)R-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 A(2A)R-D2R receptor-receptor interactions in bioluminescence resonance energy transfer (BRET) and proximity ligation assays. Peptides corresponding to TM-IV and TM-V of the A(2A)R blocked heterodimer interactions and disrupted the allosteric effect of A(2A)R activation on D2R agonist binding. Protein-protein docking was used to construct a model of the A(2A)R-D2R heterodimer with a TM-IV/V interface, which was refined using molecular dynamics simulations. Mutations in the predicted interface reduced A(2A)R-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 A(2A)R-D2R interface can be extended to study the many other G protein-coupled receptors that engage in heteroreceptor complexes.
Ämnesord
- NATURVETENSKAP -- Biologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
Nyckelord
- G protein-coupled receptor
- D-2 dopamine receptor
- A(2A) adenosine receptor
- heteroreceptor complex
- dimerization
- dimer interface
- allosteric modulation
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
Hitta via bibliotek
Till lärosätets databas