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Publication Abstract from PubMed

The adenosine A2A receptor (A2AR) plays a key role in transmembrane signalling mediated by the endogenous agonist adenosine. Here we describe the crystal structure of human A2AR thermostabilised in an active-like conformation (A2AR-GL31) bound to the selective agonist CGS21680 at a resolution of 2.6 A. The adenosine moiety of CGS21680 binds to A2AR in an identical fashion, within experimental error, to the adenosine moiety in NECA, UK432097 and adenosine itself. However, an extension in CGS21680 compared to adenosine, the (2-carboxyethyl)phenylethylamino group, binds in an extended vestibule formed from transmembrane regions 2 and 7 (TM2 and TM7), and extracellular loops 2 and 3 (EL2 and EL3). The (2-carboxyethyl)phenylethylamino group makes van der Waals contacts with the side chains of amino acid residues Glu169EL2, His264EL3, Leu2677.32, and Ile2747.39, and the amine group forms a hydrogen bond with the side chain of Ser672.65. Of these residues, only Ile2747.39 is absolutely conserved across the human adenosine receptor subfamily. The major difference between the structures of A2AR bound to either adenosine or CGS21680 is that the binding pocket narrows at the extracellular surface when CGS21680 is bound, due to an inward tilt of TM2 in that region. This conformation is stabilised by hydrogen bonds formed by the side chain of Ser672.65 to CGS21680, either directly or via an ordered water molecule. Mutation of amino acid residues Ser672.65, Glu169EL2 and His264EL3, and analysis of receptor activation either in the presence or absence of ligands, implicates this region in modulating the level of basal activity of A2AR.

Molecular Determinants of CGS21680 Binding to the Human Adenosine A2A Receptor.,Lebon G, Edwards PC, Leslie AG, Tate CG Mol Pharmacol. 2015 Mar 11. pii: mol.114.097360. PMID:25762024^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.