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Papers of the Week

Papers: 25 Jan 2020 - 31 Jan 2020

Pharmacology/Drug Development

2020 03 03




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


Lamichhane R, Liu JJ, White KL, Katritch V, Stevens RC, Wüthrich K, Millar DP
Structure. 2020 03 03; 28(3):371-377.e3.
PMID: 31978323.


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 β-adrenergic receptor (βAR) 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.