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Science 318 (5854): 1258-1265

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

High-Resolution Crystal Structure of an Engineered Human β2-Adrenergic G Protein–Coupled Receptor

Vadim Cherezov,1,* Daniel M. Rosenbaum,2,* Michael A. Hanson,1 Søren G. F. Rasmussen,2 Foon Sun Thian,2 Tong Sun Kobilka,2 Hee-Jung Choi,2,3 Peter Kuhn,4 William I. Weis,2,3 Brian K. Kobilka,2{dagger} Raymond C. Stevens1{dagger}

Abstract: Heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors constitute the largest family of eukaryotic signal transduction proteins that communicate across the membrane. We report the crystal structure of a human β2-adrenergic receptor–T4 lysozyme fusion protein bound to the partial inverse agonist carazolol at 2.4 angstrom resolution. The structure provides a high-resolution view of a human G protein–coupled receptor bound to a diffusible ligand. Ligand-binding site accessibility is enabled by the second extracellular loop, which is held out of the binding cavity by a pair of closely spaced disulfide bridges and a short helical segment within the loop. Cholesterol, a necessary component for crystallization, mediates an intriguing parallel association of receptor molecules in the crystal lattice. Although the location of carazolol in the β2-adrenergic receptor is very similar to that of retinal in rhodopsin, structural differences in the ligand-binding site and other regions highlight the challenges in using rhodopsin as a template model for this large receptor family.

1 Department of Molecular Biology, Scripps Research Institute, La Jolla, CA 92037, USA.
2 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
3 Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
4 Department of Cell Biology, Scripps Research Institute, 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.); kobilka{at}stanford.edu (B.K.K.)


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J. Hu, D. Thor, Y. Zhou, T. Liu, Y. Wang, S. M. McMillin, R. Mistry, R. A. J. Challiss, S. Costanzi, and J. Wess (2012)
FASEB J 26, 604-616
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Differential sensitivity of types 1 and 2 cholecystokinin receptors to membrane cholesterol.
R. M. Potter, K. G. Harikumar, S. V. Wu, and L. J. Miller (2012)
J. Lipid Res. 53, 137-148
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The Significance of G Protein-Coupled Receptor Crystallography for Drug Discovery.
J. A. Salon, D. T. Lodowski, and K. Palczewski (2011)
Pharmacol. Rev. 63, 901-937
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Identification of a Novel Allosteric Binding Site in the CXCR2 Chemokine Receptor.
P. de Kruijf, H. D. Lim, L. Roumen, V. A. Renjaan, J. Zhao, M. L. Webb, D. S. Auld, J. C. H. M. Wijkmans, G. J. R. Zaman, M. J. Smit, et al. (2011)
Mol. Pharmacol. 80, 1108-1118
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Activation mechanism of the {beta}2-adrenergic receptor.
R. O. Dror, D. H. Arlow, P. Maragakis, T. J. Mildorf, A. C. Pan, H. Xu, D. W. Borhani, and D. E. Shaw (2011)
PNAS 108, 18684-18689
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Allosteric and Orthosteric Sites in CC Chemokine Receptor (CCR5), a Chimeric Receptor Approach.
S. Thiele, A. Steen, P. C. Jensen, J. Mokrosinski, T. M. Frimurer, and M. M. Rosenkilde (2011)
J. Biol. Chem. 286, 37543-37554
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Role of the Transmembrane Domain 4/Extracellular Loop 2 Junction of the Human Gonadotropin-releasing Hormone Receptor in Ligand Binding and Receptor Conformational Selection.
R. Forfar and Z.-L. Lu (2011)
J. Biol. Chem. 286, 34617-34626
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Engineering a Prokaryotic Cys-loop Receptor with a Third Functional Domain.
R. Goyal, A. A. Salahudeen, and M. Jansen (2011)
J. Biol. Chem. 286, 34635-34642
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WDR36 acts as a scaffold protein tethering a G-protein-coupled receptor, G{alpha}q and phospholipase C{beta} in a signalling complex.
A. Cartier, A. Parent, P. Labrecque, G. Laroche, and J.-L. Parent (2011)
J. Cell Sci. 124, 3292-3304
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Identification of Essential Cannabinoid-binding Domains: STRUCTURAL INSIGHTS INTO EARLY DYNAMIC EVENTS IN RECEPTOR ACTIVATION.
J.-Y. Shim, A. C. Bertalovitz, and D. A. Kendall (2011)
J. Biol. Chem. 286, 33422-33435
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Structural Model of Ligand-G Protein-coupled Receptor (GPCR) Complex Based on Experimental Double Mutant Cycle Data: MT7 SNAKE TOXIN BOUND TO DIMERIC hM1 MUSCARINIC RECEPTOR.
C. Marquer, C. Fruchart-Gaillard, G. Letellier, E. Marcon, G. Mourier, S. Zinn-Justin, A. Menez, D. Servent, and B. Gilquin (2011)
J. Biol. Chem. 286, 31661-31675
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A Polymorphism-Specific "Memory" Mechanism in the {beta}2-Adrenergic Receptor.
A. Ahles, F. Rochais, T. Frambach, M. Bunemann, and S. Engelhardt (2011)
Science Signaling 4, ra53
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Pathway and mechanism of drug binding to G-protein-coupled receptors.
R. O. Dror, A. C. Pan, D. H. Arlow, D. W. Borhani, P. Maragakis, Y. Shan, H. Xu, and D. E. Shaw (2011)
PNAS 108, 13118-13123
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From Molecular Details of the Interplay between Transmembrane Helices of the Thyrotropin Receptor to General Aspects of Signal Transduction in Family A G-protein-coupled Receptors (GPCRs).
G. Kleinau, I. Hoyer, A. Kreuchwig, A.-K. Haas, C. Rutz, J. Furkert, C. L. Worth, G. Krause, and R. Schulein (2011)
J. Biol. Chem. 286, 25859-25871
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Molecular Basis of Secretin Docking to Its Intact Receptor Using Multiple Photolabile Probes Distributed throughout the Pharmacophore.
M. Dong, P. C.- H. Lam, D. I. Pinon, K. Hosohata, A. Orry, P. M. Sexton, R. Abagyan, and L. J. Miller (2011)
J. Biol. Chem. 286, 23888-23899
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Computational analysis of the structural mechanism of inhibition of chemokine receptor CXCR4 by small molecule antagonists.
S. P. Kawatkar, M. Yan, H. Gevariya, M. Y. Lim, S. Eisold, X. Zhu, Z. Huang, and J. An (2011)
Experimental Biology and Medicine 236, 844-850
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Human Genetic Polymorphisms in T1R1 and T1R3 Taste Receptor Subunits Affect Their Function.
M. Raliou, M. Grauso, B. Hoffmann, C. Schlegel-Le-Poupon, C. Nespoulous, H. Debat, C. Belloir, A. Wiencis, M. Sigoillot, S. Preet Bano, et al. (2011)
Chem Senses 36, 527-537
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