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Originally published in Science Express on 2 October 2008
Science 21 November 2008:
Vol. 322. no. 5905, pp. 1211 - 1217
DOI: 10.1126/science.1164772
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Research Articles

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}

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}scripps.edu

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