Extracellular ligand binding to G protein coupled receptors (GPCRs) modulates signaling by changing the conformational states of the G-protein and �-arrestin intracellular binding sites more than 30� away. Using site specific 19F NMR studies of �2-adrenergic receptor and its ligand complexes, we observed that the cytoplasmic ends of both helix VI and helix VII can be found in two major conformational states. Changes in NMR spectral line reveal that agonist binding shifts the equilibrium towards an activated state conformation in helix VI and to a lesser extent in helix VII. At the same time, �-arrestin biased ligands predominantly impact the conformational state of helix VII. Such differential changes in equilibrium of helices VI and VII suggests a structural model of biased signaling and partial agonism of pharmacologically relevant ligands. In addition, changes in conformational equilibria of the receptor correlate with the chemical structures of ligands bound. These data provide the first steps to decoding the ways receptor translate chemical space of the ligands to dynamics of intracellular surface.

Molecular basis of biased signaling in β<sub>2</sub>-adrenergic receptor by <sup>19</sup>F-NMR

243rd National Meeting (2012)

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Molecular basis of biased signaling in β2-adrenergic receptor by 19F-NMR

Molecular basis of biased signaling in β₂-adrenergic receptor by ¹⁹F-NMR