Structures of Human A 1 and A 2A Adenosine Receptors with Xanthines Reveal Determinants of Selectivity.

The adenosine A ₁ and A _2A 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-selective antagonists of adenosine receptors. Here we report the structure of a thermostabilized human A ₁ receptor at 3.3 Å resolution with PSB36, an A ₁ -selective xanthine-based antagonist. This is compared with structures of the A _2A receptor with PSB36 (2.8 Å resolution), caffeine (2.1 Å), and theophylline (2.0 Å) to highlight features of ligand recognition which are common across xanthines. The structures of A ₁ R and A _2A R were analyzed to identify the differences that are important selectivity determinants for xanthine ligands, and the role of T270 ^7.35 in A ₁ R (M270 ^7.35 in A _2A R) in conferring selectivity was confirmed by mutagenesis. The structural differences confirmed to lead to selectivity can be utilized in the design of new subtype-selective A ₁ R or A _2A R antagonists.
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