Structure of the Adenosine A 1 Receptor Reveals the Basis for Subtype Selectivity

Cell. 2017 Feb 23;168(5):867-877.e13. doi: 10.1016/j.cell.2017.01.042.

Abstract

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.

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine A1 Receptor Agonists / chemistry
  • Adenosine A1 Receptor Antagonists / chemistry
  • Allosteric Site
  • Crystallography, X-Ray
  • Drug Design
  • Humans
  • Receptor, Adenosine A1 / chemistry*
  • Receptor, Adenosine A1 / genetics
  • Receptor, Adenosine A2A / chemistry

Substances

  • Adenosine A1 Receptor Agonists
  • Adenosine A1 Receptor Antagonists
  • Receptor, Adenosine A1
  • Receptor, Adenosine A2A