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)

3 Citations (Scopus)
31 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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    Landin, E., Lovera, S., de Fabritiis, G., Kelm, S., Mercier, J., McMillan, D., Sessions, R., Taylor, R. J., Sands, Z., Joedicke, L., & Crump, M. (2019). The Aminotriazole Antagonist Cmpd-1 Stabilises a Novel Inactive State of the Adenosine 2A Receptor. Angewandte Chemie - International Edition, 58(28), 9399-9403. https://doi.org/10.1002/anie.201902852