Biased signaling pathways in β2-adrenergic receptor characterized by 19F-NMR

By Jeffrey J. Liu, R. Horst, Vsevolod Katritch, Raymond C. Stevens, Kurt Wüthrich. Science, 2012

619 citations recorded by the source corpus.

Choosing a Path The β2-adrenergic receptor (β2AR) is a G protein–coupled receptor that recognizes diverse ligands to trigger signaling in the cell. Besides binding G proteins, activated β2AR can be phosphorylated and bind arrestin, which redirects signaling to other pathways. Some β2AR ligands are “biased” in that they differentially activate G protein or arrestin signaling. Liu et al. (p. 1106, published online 19 January; see the Perspective by Sprang and Chief Elk) used 19F-NMR spectroscopy to examine conformational changes associated with a range of ligands and discovered that biased ligands caused differential shifts in equilibrium between two conformational states—the G protein binding state and the arrestin binding state—and thus provide a basis for rational design of pharmacological ligands. Selective effects of different ligands provide insights into the structural plasticity of receptor signaling. Extracellular ligand binding to G protein–coupled receptors (GPCRs) modulates G protein and β-arrestin signaling by changing the conformational states of the cytoplasmic region of the receptor. Using site-specific 19F-NMR (fluorine-19 nuclear magnetic resonance) labels in the β2-adrenergic receptor (β2AR) in complexes with various ligands, we observed that the cytoplasmic ends of helices VI and VII adopt two major conformational states. Changes in the NMR signals reveal that agonist binding primarily shifts the equilibrium toward the G protein–specific active state of helix VI. In contrast, β-arrestin–biased ligands predominantly impact the conformational states of helix VII. The selective effects of different ligands on the conformational equilibria involving helices VI and VII provide insights into the long-range structural plasticity of β2AR in partial and biased agonist signaling.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/9288d3c261965c61efce6c72dd5c44246a967708

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Citations in the corpus

Structural Features for Functional Selectivity at Serotonin Receptors (2013, background): “The structure of β2AR-Gαβγ complex, along with recent NMR and fluorescence studies of β2AR, implicate helix VI predominantly in G protein signaling, whereas conformational changes in helix VII are associated with enhanced β-arrestin signaling (18, 23, 24).”
GPCR Network: a large-scale collaboration on GPCR structure and function (2012, positive): “For example, using site-specific 19 F-NMR labels to study β 2 -AR complexes with various ligands, we observed that the cytoplasmic ends of helices VI and VII adopt two major conformational states 46 .”
The Molecular Basis of G Protein–Coupled Receptor Activation (2018, background): “[Distinct states in the presence of carazolol were not detected in the earlier study (56), which may reflect slower exchange between these two conformations in the detergent lauryl maltose neopentyl glycol (LMNG) versus DDM (60), use of non-affinity-purified material, or the use of a different probe”