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Science 335 (6072): 1106-1110

Copyright © 2012 by the American Association for the Advancement of Science

Biased Signaling Pathways in β2-Adrenergic Receptor Characterized by 19F-NMR

Jeffrey J. Liu,1,* Reto Horst,1,* Vsevolod Katritch,1 Raymond C. Stevens,1,{dagger} Kurt Wüthrich1,2,{dagger}

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 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.

1 Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
2 Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: stevens{at}scripps.edu (R.C.S.); wuthrich{at}scripps.edu (K.W.)


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