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Angew Chem Int Ed Engl. 2019 May 16. doi: 10.1002/anie.201902852. [Epub ahead of print]

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

Author information

1
School of Chemistry, University of Bristol, Cantock's Close, BS8 1TS, Bristol, UK.
2
UCB Biopharma, 1 Chemin du Foriest, 1420, Braine l'Alleud, Belgium.
3
Acellera, Barcelona Biomedical Research Park (PRBB), C/Doctor Aiguader 88, 08003, Barcelona, Spain.
4
ICREA, Passeig Lluis Companys 23, Barcelona, 08010, Spain.
5
UCB Celltech, 216 Bath Road, Slough, SL1 3WE, UK.
6
Biomedical Sciences, University of Bristol, University Walk, BS8 1TD, Bristol, UK.

Abstract

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

PMID:
31095849
DOI:
10.1002/anie.201902852

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