The 2.6 Angstrom Crystal Structure of a Human A[subscript 2A] Adenosine Receptor Bound to an Antagonist

Journal Article · Thu Jan 15 04:00:00 UTC 2009 · Science

DOI:https://doi.org/10.1126/science.1164772· OSTI ID:1007016

Jaakola, Veli-Pekka; Griffith, Mark T; Hanson, Michael A; Cherezov, Vadim; Chien, Ellen Y.T.; Lane, J Robert; IJzerman, Adriaan P; Stevens, Raymond C ^[1]

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1. Scripps

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 A{sub 2A} 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.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: USDOE
• OSTI ID: 1007016
• Journal Information: Science, Journal Name: Science Journal Issue: 11, 2008 Vol. 322; ISSN 0193-4511; ISSN SCEHDK
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

36 MATERIALS SCIENCE
ADENOSINE
CAFFEINE
CRYSTAL STRUCTURE
DISULFIDES
GUANINE
HUMAN POPULATIONS
INTEGRALS
LIGANDS
MEMBRANES
PROTEINS
RECEPTORS
RESIDUES
RESOLUTION
RHODOPSIN
SYMPATHOMIMETICS
TRYPTOPHAN