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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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Two Amino Acid Substitutions within the First External Loop of CCR5 Induce Human Immunodeficiency Virus-Blocking Antibodies in Mice and Chickens.
C. Pastori, A. Clivio, L. Diomede, R. Consonni, G. M. S. De Mori, R. Longhi, G. Colombo, and L. Lopalco (2008)
J. Virol. 82, 4125-4134
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Highlights From The Literature.
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Physiology 23, 61-63
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Role of {beta}-Adrenoceptor Signaling in Skeletal Muscle: Implications for Muscle Wasting and Disease.
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Physiol Rev 88, 729-767
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Wide Turn Diversity in Protein Transmembrane Helices Implications for G-Protein-Coupled Receptor and Other Polytopic Membrane Protein Structure and Function.
R. P. Riek, A. A. Finch, G. E. Begg, and R. M. Graham (2008)
Mol. Pharmacol. 73, 1092-1104
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Structure of the Complement Factor 5a Receptor-Ligand Complex Studied by Disulfide Trapping and Molecular Modeling.
I. S. Hagemann, D. L. Miller, J. M. Klco, G. V. Nikiforovich, and T. J. Baranski (2008)
J. Biol. Chem. 283, 7763-7775
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Multiple Roles for the C-terminal Tail of the Chemokine Scavenger D6.
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Dimerization and oligomerization of G-protein-coupled receptors: debated structures with established and emerging functions.
L. Szidonya, M. Cserzo, and L. Hunyady (2008)
J. Endocrinol. 196, 435-453
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Vertebrate Membrane Proteins: Structure, Function, and Insights from Biophysical Approaches.
D. J. Muller, N. Wu, and K. Palczewski (2008)
Pharmacol. Rev. 60, 43-78
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Conformational thermostabilization of the {beta}1-adrenergic receptor in a detergent-resistant form.
M. J. Serrano-Vega, F. Magnani, Y. Shibata, and C. G. Tate (2008)
PNAS 105, 877-882
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Site-specific Incorporation of Keto Amino Acids into Functional G Protein-coupled Receptors Using Unnatural Amino Acid Mutagenesis.
S. Ye, C. Kohrer, T. Huber, M. Kazmi, P. Sachdev, E. C.Y. Yan, A. Bhagat, U. L. RajBhandary, and T. P. Sakmar (2008)
J. Biol. Chem. 283, 1525-1533
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GPCR Engineering Yields High-Resolution Structural Insights into 2-Adrenergic Receptor Function.
D. M. Rosenbaum, V. Cherezov, M. A. Hanson, S. G. F. Rasmussen, F. S. Thian, T. S. Kobilka, H.-J. Choi, X.-J. Yao, W. I. Weis, R. C. Stevens, et al. (2007)
Science 318, 1266-1273
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