The Aminotriazole Antagonist Cmpd-1 Stabilises a Distinct Inactive State of the Adenosine 2A Receptor

Angew Chem Int Ed Engl. 2019 Jul 8;58(28):9399-9403. doi: 10.1002/anie.201902852. Epub 2019 Jun 5.


The widely expressed G-protein coupled receptors (GPCRs) are versatile signal transducer proteins that are attractive drug targets but structurally challenging to study. GPCRs undergo a number of conformational rearrangements when transitioning from the inactive to the active state but have so far been believed to adopt a fairly conserved inactive conformation. Using 19 F NMR spectroscopy and advanced molecular dynamics simulations we describe a novel inactive state of the adenosine 2A receptor which is stabilised by the aminotriazole antagonist Cmpd-1. We demonstrate that the ligand stabilises a unique conformation of helix V and present data on the putative binding mode of the compound involving contacts to the transmembrane bundle as well as the extracellular loop 2.

Keywords: G-protein coupled receptor; NMR spectroscopy; conformational flexibility; inactive state; molecular dynamics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amitrole / antagonists & inhibitors*
  • Biphenyl Compounds / metabolism*
  • Humans
  • Magnetic Resonance Spectroscopy / methods*
  • Molecular Dynamics Simulation / standards*
  • Receptor, Adenosine A2A / chemistry*


  • Biphenyl Compounds
  • Receptor, Adenosine A2A
  • p38alpha inhibitor CMPD1
  • Amitrole