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The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist

Jaakola, Veli-Pekka; Griffith, Mark T; Hanson, Michael A; Cherezov, Vadim; Chien, Ellen Y T; Lane, J Robert; Ijzerman, Adriaan P; Stevens, Raymond C

Authors

Veli-Pekka Jaakola

Mark T Griffith

Michael A Hanson

Vadim Cherezov

Ellen Y T Chien

ROB LANE ROB.LANE@NOTTINGHAM.AC.UK
Associate Professor

Adriaan P Ijzerman

Raymond C Stevens



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.

Journal Article Type Article
Publication Date Nov 21, 2008
Print ISSN 0036-8075
Publisher American Association for the Advancement of Science
Peer Reviewed Peer Reviewed
Volume 322
Issue 5905
Pages 1211-1217
APA6 Citation Jaakola, V., Griffith, M. T., Hanson, M. A., Cherezov, V., Chien, E. Y. T., Lane, J. R., …Stevens, R. C. (2008). The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist. Science, 322(5905), 1211-1217. https://doi.org/10.1126/science.1164772
DOI https://doi.org/10.1126/science.1164772
Publisher URL https://science.sciencemag.org/content/322/5905/1211
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