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Research Themes Drug discovery

Receptor bias

SBKB [doi:10.1038/sbkb.2011.87]
Featured Article - July 2012
Short description: Fluorine NMR characterization of the β2-adrenergic receptor uncovers conformational states that may bias GPCR signaling pathways.

β2AR ligands can differentially influence conformational equilibria of two parallel signaling pathways in helices VI and VII, resulting in biased signaling.
Figure courtesy of Ray Stevens.

G protein-coupled receptors (GPCRs) regulate numerous eukaryotic cell communication processes and are the targets of over 30% of current pharmaceuticals. GPCRs such as the β2-adrenergic receptor (β2AR) transmit signals from extracellular stimuli to intracellular pathways by coupling conformational changes induced by agonist binding to G protein signaling. β2AR can be phosphorylated in an alternative pathway, leading to β-arrestin-dependent signaling. A major goal is to understand the mechanisms by which ligands induce conformational changes in β2AR that lead to biased signaling toward either G protein or β-arrestin pathways.

Wüthrich, Stevens and colleagues (PSI GPCR Network ) have investigated the conformational responses of β2AR to ligand binding using an innovative approach that combines site-specific labeling with fluorine NMR spectroscopy. The authors monitored the conformational changes of β2AR by strategically placing fluorine-19 NMR probes on the cytoplasmic ends of helices VI and VII and at the C terminus of the receptor. Surprisingly, the resulting spectra of apo-β2AR individually labeled at helices VI and VII have fluorine signals that are composed of two peaks, compared to the spectrum of C-terminal-labeled β2AR that yields only one peak. The presence of two peaks suggests that conformational polymorphisms occur in β2AR at these positions.

The authors assigned the two peaks at each position to active and inactive states by comparing their relative populations in spectra of β2AR bound to a range of ligands at different temperatures. They observed that G protein-specific agonist binding shifts the relative populations toward the active state of helix VI while β-arrestin-biased ligands favor the helix VII active state, showing that the conformational equilibria at the two sites are at least partially uncoupled. By correlating the chemical structures of β2AR ligands with the changes observed in the NMR spectra, the authors suggest that the two pathways operate in parallel by differentially influencing the local conformational plasticity of the β2AR protein structure. This method may be broadly applicable to ligand design for GPCRs.

Michael A. Durney

References

  1. J.J. Liu et al. Biased signaling pathways in β2-adrenergic receptor characterized by 19F-NMR.
    Science. 335, 1106-1110 (2012). doi:10.1126/science.1215802

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