Structure of the adenosine A1 receptor reveals the basis for subtype selectivity

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The adenosine A1 receptor (A1-AR) is a G-protein-coupled receptor that plays a vital role in cardiac, renal, and neuronal processes but remains poorly targeted by current drugs. We determined a 3.2 Å crystal structure of the A1-AR bound to the selective covalent antagonist, DU172, and identified striking differences to the previously solved adenosine A2A receptor (A2A-AR) structure. Mutational and computational analysis of A1-AR revealed a distinct conformation of the second extracellular loop and a wider extracellular cavity with a secondary binding pocket that can accommodate orthosteric and allosteric ligands. We propose that conformational differences in these regions, rather than amino-acid divergence, underlie drug selectivity between these adenosine receptor subtypes. Our findings provide a molecular basis for AR subtype selectivity with implications for understanding the mechanisms governing allosteric modulation of these receptors, allowing the design of more selective agents for the treatment of ischemia-reperfusion injury, renal pathologies, and neuropathic pain.

Original languageEnglish
Pages (from-to)867-877.e13
Issue number5
Publication statusPublished - 23 Feb 2017


  • adenosine
  • allosteric modulation
  • cardiovascular disease
  • crystallography
  • drug design
  • drug discovery
  • G-protein-coupled receptor
  • ischemia-reperfusion
  • neuropathic pain
  • structural biology

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