Biased Signaling Pathways in β ₂ -Adrenergic Receptor Characterized by ¹⁹ F-NMR

TLDR

Extracellular ligand binding to G protein‑coupled receptors modulates G protein and β‑arrestin signaling by altering the conformational states of the receptor’s cytoplasmic region. The study employed site‑specific (19)F‑NMR labeling of the β(2)-adrenergic receptor in ligand complexes to observe two major conformational states of the cytoplasmic ends of helices VI and VII. Agonist binding shifts the equilibrium toward the G protein‑specific active state of helix VI, whereas β‑arrestin‑biased ligands mainly affect helix VII, revealing ligand‑dependent conformational equilibria that illuminate the long‑range structural plasticity underlying partial and biased agonist signaling.

Abstract

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 (19)F-NMR (fluorine-19 nuclear magnetic resonance) labels in the β(2)-adrenergic receptor (β(2)AR) 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 β(2)AR in partial and biased agonist signaling.