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Science 322 (5905): 1211-1217

Copyright © 2008 by the American Association for the Advancement of Science

The 2.6 Angstrom Crystal Structure of a Human A2A Adenosine Receptor Bound to an Antagonist

Veli-Pekka Jaakola,1* Mark T. Griffith,1* Michael A. Hanson,1* Vadim Cherezov,1 Ellen Y. T. Chien,1 J. Robert Lane,2 Adriaan P. IJzerman,2 Raymond C. Stevens1{dagger}

Abstract: The adenosine class of heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors (GPCRs) mediates the important role of extracellular adenosine in many physiological processes and is antagonized by caffeine. We have determined the crystal structure of the human A2A adenosine receptor, in complex with a high-affinity subtype-selective antagonist, ZM241385, to 2.6 angstrom resolution. Four disulfide bridges in the extracellular domain, combined with a subtle repacking of the transmembrane helices relative to the adrenergic and rhodopsin receptor structures, define a pocket distinct from that of other structurally determined GPCRs. The arrangement allows for the binding of the antagonist in an extended conformation, perpendicular to the membrane plane. The binding site highlights an integral role for the extracellular loops, together with the helical core, in ligand recognition by this class of GPCRs and suggests a role for ZM241385 in restricting the movement of a tryptophan residue important in the activation mechanism of the class A receptors.

1 Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037 USA.
2 Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Post Office Box 9502, 2300RA Leiden, Netherlands.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: stevens{at}

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Impact of the DRY Motif and the Missing "Ionic Lock" on Constitutive Activity and G-Protein Coupling of the Human Histamine H4 Receptor.
E. H. Schneider, D. Schnell, A. Strasser, S. Dove, and R. Seifert (2010)
J. Pharmacol. Exp. Ther. 333, 382-392
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Evolution-guided discovery and recoding of allosteric pathway specificity determinants in psychoactive bioamine receptors.
G. J. Rodriguez, R. Yao, O. Lichtarge, and T. G. Wensel (2010)
PNAS 107, 7787-7792
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Ligand Binding and Subtype Selectivity of the Human A2A Adenosine Receptor: IDENTIFICATION AND CHARACTERIZATION OF ESSENTIAL AMINO ACID RESIDUES.
V.-P. Jaakola, J. R. Lane, J. Y. Lin, V. Katritch, A. P. IJzerman, and R. C. Stevens (2010)
J. Biol. Chem. 285, 13032-13044
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Ligand-induced Rearrangements of the GABAB Receptor Revealed by Fluorescence Resonance Energy Transfer.
S. Matsushita, H. Nakata, Y. Kubo, and M. Tateyama (2010)
J. Biol. Chem. 285, 10291-10299
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Identification of Determinants of Glucose-Dependent Insulinotropic Polypeptide Receptor That Interact with N-Terminal Biologically Active Region of the Natural Ligand.
T. Yaqub, I. G. Tikhonova, J. Lattig, R. Magnan, M. Laval, C. Escrieut, C. Boulegue, C. Hewage, and D. Fourmy (2010)
Mol. Pharmacol. 77, 547-558
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A Conserved Aromatic Lock for the Tryptophan Rotameric Switch in TM-VI of Seven-transmembrane Receptors.
B. Holst, R. Nygaard, L. Valentin-Hansen, A. Bach, M. S. Engelstoft, P. S. Petersen, T. M. Frimurer, and T. W. Schwartz (2010)
J. Biol. Chem. 285, 3973-3985
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Analysis of Transmembrane Domains 1 and 4 of the Human Angiotensin II AT1 Receptor by Cysteine-scanning Mutagenesis.
L. Yan, B. J. Holleran, P. Lavigne, E. Escher, G. Guillemette, and R. Leduc (2010)
J. Biol. Chem. 285, 2284-2293
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Structural Basis of the Interaction between Chemokine Stromal Cell-derived Factor-1/CXCL12 and Its G-protein-coupled Receptor CXCR4.
Y. Kofuku, C. Yoshiura, T. Ueda, H. Terasawa, T. Hirai, S. Tominaga, M. Hirose, Y. Maeda, H. Takahashi, Y. Terashima, et al. (2009)
J. Biol. Chem. 284, 35240-35250
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Molecular Basis of Glucagon-like Peptide 1 Docking to Its Intact Receptor Studied with Carboxyl-terminal Photolabile Probes.
Q. Chen, D. I. Pinon, L. J. Miller, and M. Dong (2009)
J. Biol. Chem. 284, 34135-34144
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Position 5.46 of the Serotonin 5-HT2A Receptor Contributes to a Species-Dependent Variation for the 5-HT2C Agonist (R)-9-Ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one: Impact on Selectivity and Toxicological Evaluation.
K. J. Miller, G. Y. Wu, J. G. Varnes, P. Levesque, J. Li, D. Li, J. A. Robl, K. A. Rossi, and D. A. Wacker (2009)
Mol. Pharmacol. 76, 1211-1219
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Rastering strategy for screening and centring of microcrystal samples of human membrane proteins with a sub-10 {micro}m size X-ray synchrotron beam.
V. Cherezov, M. A. Hanson, M. T. Griffith, M. C. Hilgart, R. Sanishvili, V. Nagarajan, S. Stepanov, R. F. Fischetti, P. Kuhn, and R. C. Stevens (2009)
J R Soc Interface 6, S587-S597
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Activation Induces Structural Changes in the Liganded Angiotensin II Type 1 Receptor.
M. Clement, J. Cabana, B. J. Holleran, R. Leduc, G. Guillemette, P. Lavigne, and E. Escher (2009)
J. Biol. Chem. 284, 26603-26612
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The Magnitude of the Light-induced Conformational Change in Different Rhodopsins Correlates with Their Ability to Activate G Proteins.
H. Tsukamoto, D. L. Farrens, M. Koyanagi, and A. Terakita (2009)
J. Biol. Chem. 284, 20676-20683
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Small-molecule agonists for the thyrotropin receptor stimulate thyroid function in human thyrocytes and mice.
S. Neumann, W. Huang, S. Titus, G. Krause, G. Kleinau, A. T. Alberobello, W. Zheng, N. T. Southall, J. Inglese, C. P. Austin, et al. (2009)
PNAS 106, 12471-12476
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Probing the role of the cation-{pi} interaction in the binding sites of GPCRs using unnatural amino acids.
M. M. Torrice, K. S. Bower, H. A. Lester, and D. A. Dougherty (2009)
PNAS 106, 11919-11924
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The effect of ligand efficacy on the formation and stability of a GPCR-G protein complex.
X. J. Yao, G. Velez Ruiz, M. R. Whorton, S. G. F. Rasmussen, B. T. DeVree, X. Deupi, R. K. Sunahara, and B. Kobilka (2009)
PNAS 106, 9501-9506
   Abstract »    Full Text »    PDF »

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