Structures of Human A1 and A2A Adenosine Receptors with Xanthines Reveal Determinants of Selectivity

Structure. 2017 Aug 1;25(8):1275-1285.e4. doi: 10.1016/j.str.2017.06.012. Epub 2017 Jul 14.


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-selective antagonists of adenosine receptors. Here we report the structure of a thermostabilized human A1 receptor at 3.3 Å resolution with PSB36, an A1-selective xanthine-based antagonist. This is compared with structures of the A2A 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 A1R and A2AR were analyzed to identify the differences that are important selectivity determinants for xanthine 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 the design of new subtype-selective A1R or A2AR antagonists.

Keywords: PSB36; adenosine A1 receptor structure; adenosine A2A receptor structure; caffeine; theophylline; xanthine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Caffeine / chemistry
  • Caffeine / pharmacology*
  • HEK293 Cells
  • Humans
  • Molecular Docking Simulation
  • Protein Binding
  • Receptor, Adenosine A1 / chemistry*
  • Receptor, Adenosine A1 / metabolism
  • Receptor, Adenosine A2A / chemistry*
  • Receptor, Adenosine A2A / metabolism
  • Substrate Specificity
  • Theophylline / chemistry
  • Theophylline / pharmacology*


  • Receptor, Adenosine A1
  • Receptor, Adenosine A2A
  • Caffeine
  • Theophylline