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Science 318 (5854): 1266-1273

Copyright © 2007 by the American Association for the Advancement of Science

GPCR Engineering Yields High-Resolution Structural Insights into β2-Adrenergic Receptor Function

Daniel M. Rosenbaum,1,* Vadim Cherezov,2,* Michael A. Hanson,2 Søren G. F. Rasmussen,1 Foon Sun Thian,1 Tong Sun Kobilka,1 Hee-Jung Choi,1,3 Xiao-Jie Yao,1 William I. Weis,1,3 Raymond C. Stevens,2{dagger} Brian K. Kobilka1{dagger}

Abstract: The β2-adrenergic receptor (β2AR) is a well-studied prototype for heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors (GPCRs) that respond to diffusible hormones and neurotransmitters. To overcome the structural flexibility of the β2AR and to facilitate its crystallization, we engineered a β2AR fusion protein in which T4 lysozyme (T4L) replaces most of the third intracellular loop of the GPCR ("β2AR-T4L") and showed that this protein retains near-native pharmacologic properties. Analysis of adrenergic receptor ligand-binding mutants within the context of the reported high-resolution structure of β2AR-T4L provides insights into inverse-agonist binding and the structural changes required to accommodate catecholamine agonists. Amino acids known to regulate receptor function are linked through packing interactions and a network of hydrogen bonds, suggesting a conformational pathway from the ligand-binding pocket to regions that interact with G proteins.

1 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
2 Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
3 Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.

* These authors contributed equally to this work.

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


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Conformational Toggle Switches Implicated in Basal Constitutive and Agonist-Induced Activated States of 5-Hydroxytryptamine-4 Receptors.
L. P. Pellissier, J. Sallander, M. Campillo, F. Gaven, E. Queffeulou, M. Pillot, A. Dumuis, S. Claeysen, J. Bockaert, and L. Pardo (2009)
Mol. Pharmacol. 75, 982-990
   Abstract »    Full Text »    PDF »
Anterograde Trafficking of G Protein-Coupled Receptors: Function of the C-Terminal F(X)6LL Motif in Export from the Endoplasmic Reticulum.
M. T. Duvernay, C. Dong, X. Zhang, F. Zhou, C. D. Nichols, and G. Wu (2009)
Mol. Pharmacol. 75, 751-761
   Abstract »    Full Text »    PDF »
Identification of two distinct inactive conformations of the {beta}2-adrenergic receptor reconciles structural and biochemical observations.
R. O. Dror, D. H. Arlow, D. W. Borhani, M. O. Jensen, S. Piana, and D. E. Shaw (2009)
PNAS 106, 4689-4694
   Abstract »    Full Text »    PDF »
Fluorescence Resonance Energy Transfer Analysis of {alpha}2a-Adrenergic Receptor Activation Reveals Distinct Agonist-Specific Conformational Changes.
A. Zurn, U. Zabel, J.-P. Vilardaga, H. Schindelin, M. J. Lohse, and C. Hoffmann (2009)
Mol. Pharmacol. 75, 534-541
   Abstract »    Full Text »    PDF »
Molecular Basis for the Selective Interaction of Synthetic Agonists with the Human Histamine H1-Receptor Compared with the Guinea Pig H1-Receptor.
A. Strasser, H.-J. Wittmann, M. Kunze, S. Elz, and R. Seifert (2009)
Mol. Pharmacol. 75, 454-465
   Abstract »    Full Text »    PDF »
Detergent binding explains anomalous SDS-PAGE migration of membrane proteins.
A. Rath, M. Glibowicka, V. G. Nadeau, G. Chen, and C. M. Deber (2009)
PNAS 106, 1760-1765
   Abstract »    Full Text »    PDF »
Two Arginine-Glutamate Ionic Locks Near the Extracellular Surface of FFAR1 Gate Receptor Activation.
C. S. Sum, I. G. Tikhonova, S. Costanzi, and M. C. Gershengorn (2009)
J. Biol. Chem. 284, 3529-3536
   Abstract »    Full Text »    PDF »
PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling activity.
C. Monnier, C. Dode, L. Fabre, L. Teixeira, G. Labesse, J.-P. Pin, J.-P. Hardelin, and P. Rondard (2009)
Hum. Mol. Genet. 18, 75-81
   Abstract »    Full Text »    PDF »
Overlapping Binding Site for the Endogenous Agonist, Small-Molecule Agonists, and Ago-allosteric Modulators on the Ghrelin Receptor.
B. Holst, T. M. Frimurer, J. Mokrosinski, T. Halkjaer, K. B. Cullberg, C. R. Underwood, and T. W. Schwartz (2009)
Mol. Pharmacol. 75, 44-59
   Abstract »    Full Text »    PDF »
Functional Selectivity of GPCR Ligand Stereoisomers: New Pharmacological Opportunities.
R. Seifert and S. Dove (2009)
Mol. Pharmacol. 75, 13-18
   Abstract »    Full Text »    PDF »
The 2.6 Angstrom Crystal Structure of a Human A2A Adenosine Receptor Bound to an Antagonist.
V.-P. Jaakola, M. T. Griffith, M. A. Hanson, V. Cherezov, E. Y. T. Chien, J. R. Lane, A. P. IJzerman, and R. C. Stevens (2008)
Science 322, 1211-1217
   Abstract »    Full Text »    PDF »
Structural Constraints for the Binding of Short Peptides to Claudin-4 Revealed by Surface Plasmon Resonance.
J. Ling, H. Liao, R. Clark, M. S. M. Wong, and D. D. Lo (2008)
J. Biol. Chem. 283, 30585-30595
   Abstract »    Full Text »    PDF »
Role of Key Transmembrane Residues in Agonist and Antagonist Actions at the Two Conformations of the Human {beta}1-Adrenoceptor.
J. G. Baker, R. G. W. Proudman, N. C. Hawley, P. M. Fischer, and S. J. Hill (2008)
Mol. Pharmacol. 74, 1246-1260
   Abstract »    Full Text »    PDF »
Full Pharmacological Efficacy of a Novel S1P1 Agonist That Does Not Require S1P-Like Headgroup Interactions.
P. J. Gonzalez-Cabrera, E. Jo, M. G. Sanna, S. Brown, N. Leaf, D. Marsolais, M.-T. Schaeffer, J. Chapman, M. Cameron, M. Guerrero, et al. (2008)
Mol. Pharmacol. 74, 1308-1318
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Phenylalanine 169 in the Second Extracellular Loop of the Human Histamine H4 Receptor Is Responsible for the Difference in Agonist Binding between Human and Mouse H4 Receptors.
H. D. Lim, A. Jongejan, R. A. Bakker, E. Haaksma, I. J. P. de Esch, and R. Leurs (2008)
J. Pharmacol. Exp. Ther. 327, 88-96
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Structural Basis of CXCR4 Sulfotyrosine Recognition by the Chemokine SDF-1/CXCL12.
C. T. Veldkamp, C. Seibert, F. C. Peterson, N. B. De la Cruz, J. C. Haugner III, H. Basnet, T. P. Sakmar, and B. F. Volkman (2008)
Science Signaling 1, ra4
   Abstract »    Full Text »    PDF »
Ligand-Specific Contribution of the N Terminus and E2-Loop to Pharmacological Properties of the Histamine H1-Receptor.
A. Strasser, H.-J. Wittmann, and R. Seifert (2008)
J. Pharmacol. Exp. Ther. 326, 783-791
   Abstract »    Full Text »    PDF »
Mutational Analysis of the Conserved Asp2.50 and ERY Motif Reveals Signaling Bias of the Urotensin II Receptor.
C. D. Proulx, B. J. Holleran, A. A. Boucard, E. Escher, G. Guillemette, and R. Leduc (2008)
Mol. Pharmacol. 74, 552-561
   Abstract »    Full Text »    PDF »
Crystal Structure of Squid Rhodopsin with Intracellularly Extended Cytoplasmic Region.
T. Shimamura, K. Hiraki, N. Takahashi, T. Hori, H. Ago, K. Masuda, K. Takio, M. Ishiguro, and M. Miyano (2008)
J. Biol. Chem. 283, 17753-17756
   Abstract »    Full Text »    PDF »

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