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Activation of the α2B adrenoceptor by the sedative sympatholytic dexmedetomidine


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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Fig. 1: Cryo-EM structure of the α2BAR–GoA complex.
Fig. 2: Comparison of agonist-binding pockets for α2BAR and β2AR.
Fig. 3: MD simulations of α2BAR after removing both dexmedetomidine and Go from the complex.
Fig. 4: Comparison of the receptor–G protein binding interfaces of the β2AR–Gs, α2BAR–GoA and µOR–Gi1 complexes.

Data availability

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.

Code availability

The AutoEMation2.0 package is available upon request from J. Lei at Tsinghua University.


  1. 1.

    Lefkowitz, R. J. Seven transmembrane receptors: something old, something new. Acta Physiol. (Oxf.) 190, 9–19 (2007).

    CAS  Google Scholar 

  2. 2.

    Rasmussen, S. G. F. et al. Crystal structure of the β2 adrenergic receptor–Gs protein complex. Nature 477, 549–555 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Rosenbaum, D. M. et al. GPCR engineering yields high-resolution structural insights into 2-adrenergic receptor function. Science 318, 1266–1273 (2007).

    CAS  PubMed  Google Scholar 

  4. 4.

    Ring, A. M. et al. Adrenaline-activated structure of β2-adrenoceptor stabilized by an engineered nanobody. Nature 502, 575–579 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Giovannoni, M. P., Ghelardini, C., Vergelli, C. & Dal Piaz, V. α2-agonists as analgesic agents. Med. Res. Rev. 29, 339–368 (2009).

    CAS  PubMed  Google Scholar 

  6. 6.

    Hein, L. Adrenoceptors and signal transduction in neurons. Cell Tissue Res. 326, 541–551 (2006).

    CAS  PubMed  Google Scholar 

  7. 7.

    Altman, J. D. et al. Abnormal regulation of the sympathetic nervous system in α2A-adrenergic receptor knockout mice. Mol. Pharmacol. 56, 154–161 (1999).

    CAS  PubMed  Google Scholar 

  8. 8.

    Hunter, J. C. et al. Assessment of the role of α2-adrenoceptor subtypes in the antinociceptive, sedative and hypothermic action of dexmedetomidine in transgenic mice. Br. J. Pharmacol. 122, 1339–1344 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Stone, L. S., MacMillan, L. B., Kitto, K. F., Limbird, L. E. & Wilcox, G. L. The α2a adrenergic receptor subtype mediates spinal analgesia evoked by α2 agonists and is necessary for spinal adrenergic-opioid synergy. J. Neurosci. 17, 7157–7165 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Fairbanks, C. A. et al. α2C-adrenergic receptors mediate spinal analgesia and adrenergic-opioid synergy. J. Pharmacol. Exp. Ther. 300, 282–290 (2002).

    CAS  PubMed  Google Scholar 

  11. 11.

    Sawamura, S. et al. Antinociceptive action of nitrous oxide is mediated by stimulation of noradrenergic neurons in the brainstem and activation of α2B adrenoceptors. J. Neurosci. 20, 9242–9251 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Lakhlani, P. P. et al. Substitution of a mutant α2a-adrenergic receptor via ‘hit and run’ gene targeting reveals the role of this subtype in sedative, analgesic and anesthetic-sparing responses in vivo. Proc. Natl Acad. Sci. USA 94, 9950–9955 (1997).

    CAS  PubMed  Google Scholar 

  13. 13.

    Link, R. E. et al. Cardiovascular regulation in mice lacking α2-adrenergic receptor subtypes b and c. Science 273, 803–805 (1996).

    CAS  PubMed  Google Scholar 

  14. 14.

    Aantaa, R. & Jalonen, J. Perioperative use of α2-adrenoceptor agonists and the cardiac patient. Eur. J. Anaesthesiol. 23, 361–372 (2006).

    CAS  PubMed  Google Scholar 

  15. 15.

    Arcangeli, A., D’Alo, C. & Gaspari, R. Dexmedetomidine use in general anaesthesia. Curr. Drug Targets 10, 687–695 (2009).

    CAS  PubMed  Google Scholar 

  16. 16.

    Ruffolo, R. R. Jr, Bondinell, W. & Hieble, J. P. α- and β-adrenoceptors: from the gene to the clinic. 2. Structure–activity relationships and therapeutic applications. J. Med. Chem. 38, 3681–3716 (1995).

    CAS  PubMed  Google Scholar 

  17. 17.

    Jaakola, V. P. et al. Intracellularly truncated human α2B-adrenoceptors: stable and functional GPCRs for structural studies. J. Recept. Signal Transduct. Res. 25, 99–124 (2005).

    CAS  PubMed  Google Scholar 

  18. 18.

    Maeda, S. et al. Development of an antibody fragment that stabilizes GPCR/G-protein complexes. Nat. Commun. 9, 3712 (2018).

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    Maeda, S., Qu, Q., Robertson, M. J., Skiniotis, G. & Kobilka, B. K. Structures of the M1 and M2 muscarinic acetylcholine receptor/G-protein complexes. Science 364, 552–557 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Scheres, S. H. RELION: implementation of a bayesian approach to cryo-EM structure determination. J. Struct. Biol. 180, 519–530 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D 66, 213–221 (2010).

    CAS  PubMed  Google Scholar 

  22. 22.

    Strader, C. D., Candelore, M. R., Hill, W. S., Sigal, I. S. & Dixon, R. A. Identification of two serine residues involved in agonist activation of the β-adrenergic receptor. J. Biol. Chem. 264, 13572–13578 (1989).

    CAS  PubMed  Google Scholar 

  23. 23.

    Pauwels, P. J. & Colpaert, F. C. Disparate ligand-mediated Ca2+ responses by wild-type, mutant Ser200Ala and Ser204Ala α2A-adrenoceptor: Gα15 fusion proteins: evidence for multiple ligand-activation binding sites. Br. J. Pharmacol. 130, 1505–1512 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Chen, S. et al. Phe310 in transmembrane VI of the α1B-adrenergic receptor is a key switch residue involved in activation and catecholamine ring aromatic bonding. J. Biol. Chem. 274, 16320–16330 (1999).

    CAS  PubMed  Google Scholar 

  25. 25.

    Schwinn, D. A., Correa-Sales, C., Page, S. O. & Maze, M. Functional effects of activation of alpha-1 adrenoceptors by dexmedetomidine: in vivo and in vitro studies. J. Pharmacol. Exp. Ther. 259, 1147–1152 (1991).

    CAS  PubMed  Google Scholar 

  26. 26.

    Isberg, V. et al. Generic GPCR residue numbers—aligning topology maps while minding the gaps. Trends Pharmacol. Sci. 36, 22–31 (2015).

    CAS  PubMed  Google Scholar 

  27. 27.

    Eason, M. G., Kurose, H., Holt, B. D., Raymond, J. R. & Liggett, S. B. Simultaneous coupling of α2-adrenergic receptors to two G-proteins with opposing effects. Subtype-selective coupling of α2C10, α2C4 and α2C2 adrenergic receptors to Gi and Gs. J. Biol. Chem. 267, 15795–15801 (1992).

    CAS  PubMed  Google Scholar 

  28. 28.

    Xiao, R. P. et al. Coupling of β2-adrenoceptor to Gi proteins and its physiological relevance in murine cardiac myocytes. Circ. Res. 84, 43–52 (1999).

    CAS  PubMed  Google Scholar 

  29. 29.

    Carpenter, B., Nehme, R., Warne, T., Leslie, A. G. & Tate, C. G. Erratum. Structure of the adenosine A2A receptor bound to an engineered G protein. Nature 538, 542 (2016).

    PubMed  Google Scholar 

  30. 30.

    Thal, D. M., Glukhova, A., Sexton, P. M. & Christopoulos, A. Structural insights into G-protein-coupled receptor allostery. Nature 559, 45–53 (2018).

    CAS  PubMed  Google Scholar 

  31. 31.

    Garcia-Nafria, J. & Tate, C. G. Cryo-EM structures of GPCRs coupled to Gs, Gi and Go. Mol. Cell. Endocrinol. 488, 1–13 (2019).

    CAS  PubMed  Google Scholar 

  32. 32.

    Connor, M. & Christie, M. D. Opioid receptor signalling mechanisms. Clin. Exp. Pharmacol. Physiol. 26, 493–499 (1999).

    CAS  PubMed  Google Scholar 

  33. 33.

    Garcia-Nafria, J., Lee, Y., Bai, X., Carpenter, B. & Tate, C. G. Cryo-EM structure of the adenosine A2A receptor coupled to an engineered heterotrimeric G protein. Elife 7, e35946 (2018).

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Zhang, Y. et al. Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein. Nature 546, 248–253 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Liang, Y.-L. et al. Phase-plate cryo-EM structure of a class B GPCR–G-protein complex. Nature 546, 118–123 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Gregorio, G. G. et al. Single-molecule analysis of ligand efficacy in β2AR–G-protein activation. Nature 547, 68–73 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Liu, X. et al. Structural insights into the process of GPCR–G protein complex formation. Cell 177, 1243–1251 (2019).

    CAS  PubMed  Google Scholar 

  38. 38.

    Du, Y. et al. Assembly of a GPCR–G protein complex. Cell 177, 1232–1242 (2019).

    CAS  PubMed  Google Scholar 

  39. 39.

    Kato, H. E. et al. Conformational transitions of a neurotensin receptor 1–Gi1 complex. Nature 572, 80–85 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Li, X. et al. Electron counting and beam-induced motion correction enable near-atomic-resolution single-particle cryo-EM. Nat. Methods 10, 584–590 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Zheng, S. Q. et al. MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy. Nat. Methods 14, 331–332 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Mindell, J. A. & Grigorieff, N. Accurate determination of local defocus and specimen tilt in electron microscopy. J. Struct. Biol. 142, 334–347 (2003).

    PubMed  Google Scholar 

  43. 43.

    Pettersen, E. F. et al. UCSF Chimera—a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605–1612 (2004).

    CAS  PubMed  Google Scholar 

  44. 44.

    Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D Biol. Crystallogr. 60, 2126–2132 (2004).

    PubMed  Google Scholar 

  45. 45.

    Sali, A. & Blundell, T. L. Comparative protein modelling by satisfaction of spatial restraints. J. Mol. Biol. 234, 779–815 (1993).

    CAS  PubMed  Google Scholar 

  46. 46.

    Ghanouni, P. et al. The effect of pH on β2 adrenoceptor function. Evidence for protonation-dependent activation. J. Biol. Chem. 275, 3121–3127 (2000).

    CAS  PubMed  Google Scholar 

  47. 47.

    Wolf, M. G., Hoefling, M., Aponte-Santamaria, C., Grubmuller, H. & Groenhof, G. g_membed: efficient insertion of a membrane protein into an equilibrated lipid bilayer with minimal perturbation. J. Comput. Chem. 31, 2169–2174 (2010).

    CAS  PubMed  Google Scholar 

  48. 48.

    Case, D. A. et al. AMBER18 (Univ. California, 2018).

  49. 49.

    Wang, J., Wolf, R. M., Caldwell, J. W., Kollman, P. A. & Case, D. A. Development and testing of a general amber force field. J. Comput. Chem. 25, 1157–1174 (2004).

    CAS  PubMed  Google Scholar 

  50. 50.

    Dickson, C. J. et al. Lipid14: the AMBER lipid force field. J. Chem. Theory Comput. 10, 865–879 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Maier, J. A. et al. ff14SB: improving the accuracy of protein side chain and backbone parameters from ff99SB. J. Chem. Theory Comput. 11, 3696–3713 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Bayly, C. I., Cieplak, P., Cornell, W. D. & Kollman, P. A. A well-behaved electrostatic potential based method using charge restraints for deriving atomic charges—the RESP model. J. Phys. Chem. 97, 10269–10280 (1993).

    CAS  Google Scholar 

  53. 53.

    Fanelli, F. Dimerization of the lutropin receptor: insights from computational modeling. Mol. Cell. Endocrinol. 260–262, 59–64 (2007).

    PubMed  Google Scholar 

  54. 54.

    Van Der Spoel, D. et al. GROMACS: fast, flexible and free. J. Comput. Chem. 26, 1701–1718 (2005).

    Google Scholar 

  55. 55.

    Abraham, M. J. et al. GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers. Softwarex 1–2, 19–25 (2015).

    Google Scholar 

  56. 56.

    Hess, B., Bekker, H., Berendsen, H. J. C. & Fraaije, J. G. E. M. LINCS: A linear constraint solver for molecular simulations. J. Comput. Chem. 18, 1463–1472 (1997).

  57. 57.

    Darden, T., York, D. & Pedersen, L. Particle mesh Ewald: an Nlog(N) method for Ewald sums in large systems. J. Chem. Phys. 98, 10089–10092 (1993).

    CAS  Google Scholar 

  58. 58.

    Roe, D. R. & Cheatham, T. E. III PTRAJ and CPPTRAJ: software for processing and analysis of molecular dynamics trajectory data. J. Chem. Theory Comput. 9, 3084–3095 (2013).

    CAS  PubMed  Google Scholar 

  59. 59.

    Hunter, J. D. Matplotlib: a 2D graphics environment. Comput. Sci. Eng. 9, 90–95 (2007).

    Google Scholar 

  60. 60.

    Hanwell, M. D. et al. Avogadro: an advanced semantic chemical editor, visualization and analysis platform. J. Cheminform. 4, 17 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Trott, O. & Olson, A. J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J. Comput. Chem. 31, 455–461 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

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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.

Author information




D.Y., J.Z., X.S. and J.X. purified α2BAR and G proteins. D.Y. purified scFv16, prepared the α2BAR complexes, and modeled and refined the structures from cryo-EM density maps. Z.L. and D.Y. obtained cryo-EM data, and Z.L. processed the cryo-EM data under the supervision of H.-W.W. J.K. performed MD simulations. S.M. identified and assisted with scFV16 purification. B.K.K. and D.Y. wrote the manuscript with input from all the authors. B.K.K., H.-W.W. and P.G. supervised the project.

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Correspondence to Peter Gmeiner, Hong-Wei Wang or Brian K. Kobilka.

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B.K.K. is co-founder of and consultant for ConfometRx.

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Supplementary Figs. 1–14 and Tables 1–2.

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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).

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