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  Biased Signaling of the G-Protein-Coupled Receptor beta(2)AR Is Governed by Conformational Exchange Kinetics

Lamichhane, R., Liu, J. J., White, K. L., Katritch, V., Stevens, R. C., Wuthrich, K., et al. (2020). Biased Signaling of the G-Protein-Coupled Receptor beta(2)AR Is Governed by Conformational Exchange Kinetics. STRUCTURE, 28(3), 371-377. doi:10.1016/j.str.2020.01.001.

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 Creators:
Lamichhane, Rajan1, Author
Liu, Jeffrey J.2, Author              
White, Kate L.1, Author
Katritch, Vsevolod1, Author
Stevens, Raymond C.1, Author
Wuthrich, Kurt1, Author
Millar, David P.1, Author
Affiliations:
1external, ou_persistent22              
2Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              

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Free keywords: SINGLE-MOLECULE FRET; STRUCTURAL INSIGHTS; CRYSTAL-STRUCTURE; LIGAND EFFICACY; ARRESTIN; RECONSTITUTION; AGONISTS; TARGETS
 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 beta-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 beta-arrestin activation is associated with transmembrane helix VII (TM VII) of GPCRs. Here, single-molecule fluorescence spectroscopy with the beta(2)-adrenergic receptor (beta(2)AR) in the ligand-free state showed that TM VII spontaneously fluctuates between one inactive and one active-like conformation. The presence of the beta-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.

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Language(s): eng - English
 Dates: 2020
 Publication Status: Published in print
 Pages: 10
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: ISI: 000518466100013
DOI: 10.1016/j.str.2020.01.001
 Degree: -

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Title: STRUCTURE
Source Genre: Journal
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Publ. Info: 50 HAMPSHIRE ST, FLOOR 5, CAMBRIDGE, MA 02139 USA : CELL PRESS
Pages: - Volume / Issue: 28 (3) Sequence Number: - Start / End Page: 371 - 377 Identifier: ISSN: 0969-2126