This title appears in the Scientific Report :
2023
Please use the identifier:
http://dx.doi.org/10.34734/FZJ-2024-00721 in citations.
Please use the identifier: http://dx.doi.org/10.1038/s42003-023-04727-z in citations.
Sub-millisecond conformational dynamics of the A2A adenosine receptor revealed by single-molecule FRET
Sub-millisecond conformational dynamics of the A2A adenosine receptor revealed by single-molecule FRET
The complex pharmacology of G-protein-coupled receptors (GPCRs) is defined by their multi-state conformational dynamics. Single-molecule Förster Resonance Energy Transfer (smFRET) is well suited to quantify dynamics for individual protein molecules; however, its application to GPCRs is challenging....
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Personal Name(s): | Maslov, Ivan |
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Volkov, Oleksandr / Khorn, Polina / Orekhov, Philipp / Gusach, Anastasiia / Kuzmichev, Pavel / Gerasimov, Andrey / Luginina, Aleksandra / Coucke, Quinten / Bogorodskiy, Andrey / Gordeliy, Valentin / Wanninger, Simon / Barth, Anders / Mishin, Alexey / Hofkens, Johan / Cherezov, Vadim / Gensch, Thomas / Hendrix, Jelle (Corresponding author) / Borshchevskiy, Valentin (Corresponding author) | |
Contributing Institute: |
Strukturbiochemie; IBI-7 Molekular- und Zellphysiologie; IBI-1 |
Published in: | Communications biology, 6 (2023) 1, S. 362 |
Imprint: |
London
Springer Nature
2023
|
DOI: |
10.34734/FZJ-2024-00721 |
DOI: |
10.1038/s42003-023-04727-z |
Document Type: |
Journal Article |
Research Program: |
Information Processing in Neuronal Networks |
Link: |
OpenAccess |
Publikationsportal JuSER |
Please use the identifier: http://dx.doi.org/10.1038/s42003-023-04727-z in citations.
The complex pharmacology of G-protein-coupled receptors (GPCRs) is defined by their multi-state conformational dynamics. Single-molecule Förster Resonance Energy Transfer (smFRET) is well suited to quantify dynamics for individual protein molecules; however, its application to GPCRs is challenging. Therefore, smFRET has been limited to studies of inter-receptor interactions in cellular membranes and receptors in detergent environments. Here, we performed smFRET experiments on functionally active human A2A adenosine receptor (A2AAR) molecules embedded in freely diffusing lipid nanodiscs to study their intramolecular conformational dynamics. We propose a dynamic model of A2AAR activation that involves a slow (>2 ms) exchange between the active-like and inactive-like conformations in both apo and antagonist-bound A2AAR, explaining the receptor’s constitutive activity. For the agonist-bound A2AAR, we detected faster (390 ± 80 µs) ligand efficacy-dependent dynamics. Our work establishes a general smFRET platform for GPCR investigations that can potentially be used for drug screening and/or mechanism-of-action studies. |