Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

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} (R.C.S.); wuthrich{at} (K.W.)

Functional map of arrestin-1 at single amino acid resolution.
M. K. Ostermaier, C. Peterhans, R. Jaussi, X. Deupi, and J. Standfuss (2014)
PNAS 111, 1825-1830
   Abstract »    Full Text »    PDF »
Identification of Novel Functionally Selective {kappa}-Opioid Receptor Scaffolds.
K. L. White, A. P. Scopton, M.-L. Rives, R. V. Bikbulatov, P. R. Polepally, P. J. Brown, T. Kenakin, J. A. Javitch, J. K. Zjawiony, and B. L. Roth (2014)
Mol. Pharmacol. 85, 83-90
   Abstract »    Full Text »    PDF »
Chemotype-selective Modes of Action of {kappa}-Opioid Receptor Agonists.
E. Vardy, P. D. Mosier, K. J. Frankowski, H. Wu, V. Katritch, R. B. Westkaemper, J. Aube, R. C. Stevens, and B. L. Roth (2013)
J. Biol. Chem. 288, 34470-34483
   Abstract »    Full Text »    PDF »
A Multiplexed Fluorescent Assay for Independent Second-Messenger Systems: Decoding GPCR Activation in Living Cells.
P. H. Tewson, A. M. Quinn, and T. E. Hughes (2013)
J Biomol Screen 18, 797-806
   Abstract »    Full Text »    PDF »
Detection of G Protein-selective G Protein-coupled Receptor (GPCR) Conformations in Live Cells.
R. U. Malik, M. Ritt, B. T. DeVree, R. R. Neubig, R. K. Sunahara, and S. Sivaramakrishnan (2013)
J. Biol. Chem. 288, 17167-17178
   Abstract »    Full Text »    PDF »
Insights into congenital stationary night blindness based on the structure of G90D rhodopsin.
A. Singhal, M. K. Ostermaier, S. A. Vishnivetskiy, V. Panneels, K. T. Homan, J. J. G. Tesmer, D. Veprintsev, X. Deupi, V. V. Gurevich, G. F. X. Schertler, et al. (2013)
EMBO Rep. 14, 520-526
   Abstract »    Full Text »    PDF »
Structural Features for Functional Selectivity at Serotonin Receptors.
D. Wacker, C. Wang, V. Katritch, G. W. Han, X.-P. Huang, E. Vardy, J. D. McCorvy, Y. Jiang, M. Chu, F. Y. Siu, et al. (2013)
Science 340, 615-619
   Abstract »    Full Text »    PDF »
Biased and Constitutive Signaling in the CC-chemokine Receptor CCR5 by Manipulating the Interface between Transmembrane Helices 6 and 7.
A. Steen, S. Thiele, D. Guo, L. S. Hansen, T. M. Frimurer, and M. M. Rosenkilde (2013)
J. Biol. Chem. 288, 12511-12521
   Abstract »    Full Text »    PDF »
Distinct Roles of {beta}-Arrestin 1 and {beta}-Arrestin 2 in ORG27569-induced Biased Signaling and Internalization of the Cannabinoid Receptor 1 (CB1).
K. H. Ahn, M. M. Mahmoud, J.-Y. Shim, and D. A. Kendall (2013)
J. Biol. Chem. 288, 9790-9800
   Abstract »    Full Text »    PDF »
Polar transmembrane interactions drive formation of ligand-specific and signal pathway-biased family B G protein-coupled receptor conformations.
D. Wootten, J. Simms, L. J. Miller, A. Christopoulos, and P. M. Sexton (2013)
PNAS 110, 5211-5216
   Abstract »    Full Text »    PDF »
Biased agonism of protease-activated receptor 1 by activated protein C caused by noncanonical cleavage at Arg46.
L. O. Mosnier, R. K. Sinha, L. Burnier, E. A. Bouwens, and J. H. Griffin (2012)
Blood 120, 5237-5246
   Abstract »    Full Text »    PDF »
Strontium Is a Biased Agonist of the Calcium-Sensing Receptor in Rat Medullary Thyroid Carcinoma 6-23 Cells.
A. R. B. Thomsen, J. Worm, S. E. Jacobsen, M. Stahlhut, M. Latta, and H. Brauner-Osborne (2012)
J. Pharmacol. Exp. Ther. 343, 638-649
   Abstract »    Full Text »    PDF »
Role of Detergents in Conformational Exchange of a G Protein-coupled Receptor.
K. Y. Chung, T. H. Kim, A. Manglik, R. Alvares, B. K. Kobilka, and R. S. Prosser (2012)
J. Biol. Chem. 287, 36305-36311
   Abstract »    Full Text »    PDF »
New Insights for Drug Design from the X-Ray Crystallographic Structures of G-Protein-Coupled Receptors.
K. A. Jacobson and S. Costanzi (2012)
Mol. Pharmacol. 82, 361-371
   Abstract »    Full Text »    PDF »
Structural Origins of Receptor Bias.
S. R. Sprang and J. C. Elk (2012)
Science 335, 1055-1056
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882