Abstract
The adenosine A1 and A2A receptors belong to the purinergic family of G protein-coupled receptors, and regulate diverse functions of the cardiovascular, respiratory, renal, inflammation, and CNS. Xanthines such as caffeine and theophylline are weak, non-selectiveantagonists of adenosine receptors. Here we report the structure of a thermostabilized human A1 receptor at 3.3Å resolution with PSB36, an A1-selectivexanthine-based antagonist. This is compared with structures of the A2A receptor with PSB36 (2.8Å resolution), caffeine (2.1Å), and theophylline (2.0Å) to highlight features of ligand recognition which are common across xanthines. The structures of A1R and A2AR were analyzed to identify the differences that are important selectivity determinants forxanthine ligands, and the role of T2707.35 in A1R (M2707.35 in A2AR) in conferring selectivity was confirmed by mutagenesis. The structural differences confirmed to lead to selectivity can be utilized in thedesign of new subtype-selective A1R or A2AR antagonists.
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