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

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)9399-9403
Number of pages5
JournalAngewandte Chemie - International Edition
Volume58
Issue number28
Early online date16 May 2019
DOIs
DateAccepted/In press - 8 May 2019
DateE-pub ahead of print - 16 May 2019
DatePublished (current) - 8 Jul 2019

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.

    Research areas

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

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  • Full-text PDF (accepted author manuscript)

    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via Wiley at https://onlinelibrary.wiley.com/doi/full/10.1002/anie.201902852. Please refer to any applicable terms of use of the publisher.

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    Embargo ends: 16/05/20

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