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

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.

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

• Journal Article Type: Article
• Acceptance Date: Sep 25, 2008
• Publication Date: Nov 21, 2008
• Deposit Date: Apr 22, 2020
• Print ISSN: 0036-8075
• Publisher: American Association for the Advancement of Science
• Peer Reviewed: Peer Reviewed
• Volume: 322
• Issue: 5905
• Pages: 1211-1217
• DOI: https://doi.org/10.1126/science.1164772
• Public URL: http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=18832607&retmode=ref&cmd=prlinks
• Publisher URL: https://science.sciencemag.org/content/322/5905/1211