The α2 adrenergic receptors (α2ARs) are G protein-coupled receptors (GPCRs) that respond to adrenaline and noradrenaline and couple to the Gi/o family of G proteins. α2ARs play important roles in regulating the sympathetic nervous system. Dexmedetomidine is a highly selective α2AR agonist used in post-operative patients as an anxiety-reducing, sedative medicine that decreases the requirement for opioids. As is typical for selective αAR agonists, dexmedetomidine consists of an imidazole ring and a substituted benzene moiety lacking polar groups, which is in contrast to βAR-selective agonists, which share an ethanolamine group and an aromatic system with polar, hydrogen-bonding substituents. To better understand the structural basis for the selectivity and efficacy of adrenergic agonists, we determined the structure of the α2BAR in complex with dexmedetomidine and Go at a resolution of 2.9 Å by single-particle cryo-EM. The structure reveals the mechanism of α2AR-selective activation and provides insights into Gi/o coupling specificity.
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All data generated or analyzed during this study are included in this Article and its Supplementary Information. Sequences of constructs used in this study are listed in Supplementary Fig. 2 and described in the Methods. Cryo-EM density maps for the α2BAR–GoA and α2BAR–Gi1 complexes have been deposited in the Electron Microscopy Data Bank (EMDB) under accession codes EMD-9911 and EMD-9912, respectively. The coordinates for models of the α2BAR–GoA and α2BAR–Gi1 complexes have been deposited in the PDB under accession nos. 6K41 and 6K42, respectively.
The AutoEMation2.0 package is available upon request from J. Lei at Tsinghua University.
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This work was supported by the Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Medicine, Tsinghua University, by grant no. 2016YFA0501100 to H.-W.W. from the Ministry of Science and Technology of China and by DFG grant GRK 1910 to P.G. and J.K. Computing resources were provided by the RRZE. We thank Y. Du, W. Huang and D. Hilger for help in protein purification and S. Han for structure analysis. We are thankful to J. Lei, X. Li, X. Li and T. Yang for providing the cryo-EM and high-performance computational facility support, and J. Wang, X. Fan, Q. Zhou, S. Sun, F. Yang and X. Pi for their technical assistance with cryo-EM data processing. We thank the Erlangen Regional Computing Center (RRZE) for computer resources and support. B.K.K. is a Chan Zuckerberg Biohub investigator and a Einstein BIH visiting fellow.
B.K.K. is co-founder of and consultant for ConfometRx.
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Yuan, D., Liu, Z., Kaindl, J. et al. Activation of the α2B adrenoceptor by the sedative sympatholytic dexmedetomidine. Nat Chem Biol 16, 507–512 (2020). https://doi.org/10.1038/s41589-020-0492-2
European Journal of Medicinal Chemistry (2021)