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

Erik Landin, Silvia Lovera, Gianni de Fabritiis, Sebastien Kelm, Joel Mercier, David McMillan, Richard Sessions, Richard J Taylor, Zara Sands, Lisa Joedicke*, Matthew Crump

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

3 Citations (Scopus)
41 Downloads (Pure)

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 19F 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.
Original languageEnglish
Pages (from-to)9399-9403
Number of pages5
JournalAngewandte Chemie - International Edition
Volume58
Issue number28
Early online date16 May 2019
DOIs
Publication statusPublished - 8 Jul 2019

Structured keywords

  • BrisSynBio
  • Bristol BioDesign Institute

Keywords

  • G-protein coupled receptor
  • NMR spectroscopy
  • molecular dynamics
  • conformational flexibility
  • inactive state
  • Synthetic biology

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