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Structure. 2020 Mar 3;28(3):371-377.e3. doi: 10.1016/j.str.2020.01.001. Epub 2020 Jan 23.

Biased Signaling of the G-Protein-Coupled Receptor β2AR Is Governed by Conformational Exchange Kinetics.

Author information

1
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
2
Departments of Biological Sciences and Chemistry, Bridge Institute, USC Michelson Center for Convergent Bioscience, University of Southern California, Childs Way, MC3502, Los Angeles, CA 90089, USA.
3
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA; Skaggs Institute of Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
4
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: millar@scripps.edu.

Abstract

G-protein-coupled receptors (GPCRs) mediate a wide range of human physiological functions by transducing extracellular ligand binding events into intracellular responses. GPCRs can activate parallel, independent signaling pathways mediated by G proteins or β-arrestins. Whereas "balanced" agonists activate both pathways equally, "biased" agonists dominantly activate one pathway, which is of interest for designing GPCR-targeting drugs because it may mitigate undesirable side effects. Previous studies demonstrated that β-arrestin activation is associated with transmembrane helix VII (TM VII) of GPCRs. Here, single-molecule fluorescence spectroscopy with the β2-adrenergic receptor (β2AR) in the ligand-free state showed that TM VII spontaneously fluctuates between one inactive and one active-like conformation. The presence of the β-arrestin-biased agonist isoetharine prolongs the dwell time of TM VII in the active-like conformation compared with the balanced agonist formoterol, suggesting that ligands can induce signaling bias by modulating the kinetics of receptor conformational exchange.

KEYWORDS:

G-protein-coupled receptor; biased signaling; conformational dynamics; single-molecule fluorescence spectroscopy; β(2)-adrenergic receptor

PMID:
31978323
DOI:
10.1016/j.str.2020.01.001

Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

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