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Published Online October 2, 2008
Science DOI: 10.1126/science.1164772

Research Articles

Submitted on August 18, 2008
Accepted on September 25, 2008

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

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

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, PO Box 9502, 2300RA Leiden, The Netherlands.

* To whom correspondence should be addressed.
Raymond C. Stevens , E-mail: stevens{at}scripps.edu

{dagger}These authors contributed equally to this work.

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.


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