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The Aminotriazole Antagonist Cmpd‐1 Stabilises a Distinct Inactive State of the Adenosine 2A Receptor
Author(s) -
Landin Erik J. B.,
Lovera Silvia,
de Fabritiis Gianni,
Kelm Sebastian,
Mercier Joël,
McMillan David,
Sessions Richard B.,
Taylor Richard J.,
Sands Zara A.,
Joedicke Lisa,
Crump Matthew P.
Publication year - 2019
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201902852
Subject(s) - g protein coupled receptor , transmembrane domain , adenosine receptor , chemistry , helix (gastropod) , stereochemistry , receptor , ligand (biochemistry) , antagonist , transmembrane protein , adenosine , biophysics , extracellular , biochemistry , biology , ecology , snail , agonist
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.