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

Erik J B Landin, Silvia Lovera, Gianni de Fabritiis, Sebastian Kelm, Joël Mercier, David McMillan, Richard B Sessions, Richard J Taylor, Zara A Sands, Lisa Joedicke, Matthew P Crump

Angewandte Chemie (International ed. in English) 2019 Jul 08

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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. © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Citation

Erik J B Landin, Silvia Lovera, Gianni de Fabritiis, Sebastian Kelm, Joël Mercier, David McMillan, Richard B Sessions, Richard J Taylor, Zara A Sands, Lisa Joedicke, Matthew P Crump. The Aminotriazole Antagonist Cmpd-1 Stabilises a Distinct Inactive State of the Adenosine 2A Receptor. Angewandte Chemie (International ed. in English). 2019 Jul 08;58(28):9399-9403