Letter | Published:

Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone

Nature volume 555, pages 269273 (08 March 2018) | Download Citation


Dopamine is a neurotransmitter that has been implicated in processes as diverse as reward, addiction, control of coordinated movement, metabolism and hormonal secretion. Correspondingly, dysregulation of the dopaminergic system has been implicated in diseases such as schizophrenia, Parkinson’s disease, depression, attention deficit hyperactivity disorder, and nausea and vomiting. The actions of dopamine are mediated by a family of five G-protein-coupled receptors1. The D2 dopamine receptor (DRD2) is the primary target for both typical2 and atypical3,4 antipsychotic drugs, and for drugs used to treat Parkinson’s disease. Unfortunately, many drugs that target DRD2 cause serious and potentially life-threatening side effects due to promiscuous activities against related receptors4,5. Accordingly, a molecular understanding of the structure and function of DRD2 could provide a template for the design of safer and more effective medications. Here we report the crystal structure of DRD2 in complex with the widely prescribed atypical antipsychotic drug risperidone. The DRD2–risperidone structure reveals an unexpected mode of antipsychotic drug binding to dopamine receptors, and highlights structural determinants that are essential for the actions of risperidone and related drugs at DRD2.

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  1. 1.

    , , , & Dopamine receptors: from structure to function. Physiol. Rev. 78, 189–225 (1998)

  2. 2.

    , & Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 192, 481–483 (1976)

  3. 3.

    , & Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J. Pharmacol. Exp. Ther. 251, 238–246 (1989)

  4. 4.

    , & Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat. Rev. Drug Discov. 3, 353–359 (2004)

  5. 5.

    Drugs and valvular heart disease. N. Engl. J. Med. 356, 6–9 (2007)

  6. 6.

    & Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science 188, 1217–1219 (1975)

  7. 7.

    & Molecular biology of dopamine receptors. Trends Pharmacol. Sci. 13, 61–69 (1992)

  8. 8.

    & The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol. Rev. 63, 182–217 (2011)

  9. 9.

    , , , & Dopamine in drug abuse and addiction: results of imaging studies and treatment implications. Arch. Neurol. 64, 1575–1579 (2007)

  10. 10.

    et al. Cloning and expression of a rat D2 dopamine receptor cDNA. Nature 336, 783–787 (1988)

  11. 11.

    et al. Cloning of the cDNA and gene for a human D2 dopamine receptor. Proc. Natl Acad. Sci. USA 86, 9762–9766 (1989)

  12. 12.

    , , , & Multiple D2 dopamine receptors produced by alternative RNA splicing. Nature 342, 926–929 (1989)

  13. 13.

    et al. Discovery of β-arrestin-biased dopamine D2 ligands for probing signal transduction pathways essential for antipsychotic efficacy. Proc. Natl Acad. Sci. USA 108, 18488–18493 (2011)

  14. 14.

    , , & Mapping the binding-site crevice of the dopamine D2 receptor by the substituted-cysteine accessibility method. Neuron 14, 825–831 (1995)

  15. 15.

    , & Structural mimicry in G protein-coupled receptors: implications of the high-resolution structure of rhodopsin for structure-function analysis of rhodopsin-like receptors. Mol. Pharmacol. 60, 1–19 (2001)

  16. 16.

    et al. Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist. Science 330, 1091–1095 (2010)

  17. 17.

    et al. D4 dopamine receptor high-resolution structures enable the discovery of selective agonists. Science 358, 381–386 (2017)

  18. 18.

    et al. Structure-based discovery of opioid analgesics with reduced side effects. Nature 537, 185–190 (2016)

  19. 19.

    , & How ligands illuminate GPCR molecular pharmacology. Cell 170, 414–427 (2017)

  20. 20.

    et al. Structure-inspired design of β-arrestin-biased ligands for aminergic GPCRs. Nat. Chem. Biol. 14, 126–134 (2018)

  21. 21.

    et al. Discovery and characterization of a G protein-biased agonist that inhibits β-arrestin recruitment to the D2 dopamine receptor. Mol. Pharmacol. 86, 96–105 (2014)

  22. 22.

    & Mechanisms of inverse agonist action at D2 dopamine receptors. Br. J. Pharmacol. 145, 34–42 (2005)

  23. 23.

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

  24. 24.

    , , , & Evidence for a model of agonist-induced activation of 5–HT2A serotonin receptors which involves the disruption of a strong ionic interaction between helices 3 and 6. J. Biol. Chem. 18, 11441–11449 (2002)

  25. 25.

    et al. Activation of the β2-adrenergic receptor involves disruption of an ionic lock between the cytoplasmic ends of transmembrane segments 3 and 6. J. Biol. Chem. 276, 29171–29177 (2001)

  26. 26.

    et al. Crystal structure of rhodopsin: a G protein-coupled receptor. Science 289, 739–745 (2000)

  27. 27.

    et al. Pharmacology of risperidone (R 64 766), a new antipsychotic with serotonin–S2 and dopamine–D2 antagonistic properties. J. Pharmacol. Exp. Ther. 244, 685–693 (1988)

  28. 28.

    , , , & Relationship between dopamine D2 occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am. J. Psychiatry 157, 514–520 (2000)

  29. 29.

    & Does fast dissociation from the dopamine D2 receptor explain the action of atypical antipsychotics?: A new hypothesis. Am. J. Psychiatry 158, 360–369 (2001)

  30. 30.

    et al. Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors. Nat. Commun. 8, 763 (2017)

  31. 31.

    et al. GPCR engineering yields high-resolution structural insights into β2-adrenergic receptor function. Science 318, 1266–1273 (2007)

  32. 32.

    & Crystallizing membrane proteins using lipidic mesophases. Nat. Protocols 4, 706–731 (2009)

  33. 33.

    , , & HKL-3000: the integration of data reduction and structure solution—from diffraction images to an initial model in minutes. Acta Crystallogr. D Biol. Crystallogr. 62, 859–866 (2006)

  34. 34.

    et al. Phaser crystallographic software. J. Appl. Crystallogr. 40, 658–674 (2007)

  35. 35.

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

  36. 36.

    , , & Features and development of Coot. Acta Crystallogr. D Biol. Crystallogr. 66, 486–501 (2010)

  37. 37.

    & The kinetics of competitive radioligand binding predicted by the law of mass action. Mol. Pharmacol. 25, 1–9 (1984)

  38. 38.

    & PROMALS3D: multiple protein sequence alignment enhanced with evolutionary and three-dimensional structural information. Methods Mol. Biol. 1079, 263–271 (2014)

  39. 39.

    & Comparative protein structure modeling using MODELLER. Curr. Protoc. Bioinformatics 47, 5 6 1–5 6 32 (2014)

  40. 40.

    , , , & Ligand pose and orientational sampling in molecular docking. PLoS One 8, e75992 (2013)

  41. 41.

    et al. The IUPHAR/BPS Guide to pharmacology in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. Nucleic Acids Res. 44 (D1), D1054–D1068 (2016)

  42. 42.

    , , & Directory of useful decoys, enhanced (DUD-E): better ligands and decoys for better benchmarking. J. Med. Chem. 55, 6582–6594 (2012)

  43. 43.

    . et al. AMBER 2015. (University of California, 2015)

  44. 44.

    , , & Asparagine and glutamine: using hydrogen atom contacts in the choice of side-chain amide orientation. J. Mol. Biol. 285, 1735–1747 (1999)

  45. 45.

    & Electrostatic contributions to heat capacity changes of DNA-ligand binding. Biophys. J. 75, 769–776 (1998)

  46. 46.

    Polyelectrolyte electrostatics: Salt dependence, entropic, and enthalpic contributions to free energy in the nonlinear Poisson–Boltzmann model. Biopolymers 36, 227–243 (1995)

  47. 47.

    & Rapid context-dependent ligand desolvation in molecular docking. J. Chem. Inf. Model. 50, 1561–1573 (2010)

  48. 48.

    , & Comparison of automatic three-dimensional model builders using 639 X-ray structures. J. Chem. Inf. Comput. Sci. 34, 1000–1008 (1994)

  49. 49.

    , , , & Conformer generation with OMEGA: algorithm and validation using high quality structures from the Protein Databank and Cambridge Structural Database. J. Chem. Inf. Model. 50, 572–584 (2010)

  50. 50.

    , , & Model for aqueous solvation based on class IV atomic charges and first solvation shell effects. J. Phys. Chem. 100, 16385–16398 (1996)

  51. 51.

    , , & New class IV charge model for extracting accurate partial charges from wave functions. J. Phys. Chem. A 102, 1820–1831 (1998)

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This work was supported by NIH Grants RO1MH61887, U19MH82441, the NIMH Psychoactive Drug Screening Program Contract and the Michael Hooker Chair for Protein Therapeutics and Translational Proteomics (to B.L.R.) and by R35GM122481 (to B.K.S.). We thank J. Sondek and S. Endo-Streeter for providing independent structure quality control analysis; M. J. Miley and the UNC macromolecular crystallization core for advice and use of their equipment for crystal harvesting and transport, which is supported by the National Cancer Institute under award number P30CA016086; B. E. Krumm for advice on data processing and help with thermostabilization assays; and the staff of GM/CA@APS, which has been funded with Federal funds from the National Cancer Institute (ACB-12002) and the National Institute of General Medical Sciences (AGM-12006). This research used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science user facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357.

Author information


  1. Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7365, USA

    • Sheng Wang
    • , Tao Che
    • , Daniel Wacker
    •  & Bryan L. Roth
  2. Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158-2280, USA

    • Anat Levit
    •  & Brian K. Shoichet
  3. Division of Chemical Biology & Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7360, USA

    • Bryan L. Roth
  4. National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7365, USA

    • Bryan L. Roth


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S.W. designed experiments, developed the DRD2 construct and purification, expressed, purified and crystallized the receptor, collected diffraction data, solved and refined the structure, analysed the structure, performed radioligand binding and prepared the manuscript. T.C. performed radioligand binding, analysed the data and assisted with preparing the manuscript. A.L. conducted the homology modelling and docking and helped to edit the manuscript. B.K.S. supervised the modelling and docking and helped to prepare the manuscript. D.W. refined and analysed the structure, supervised the structure determination and assisted with preparing the manuscript. B.L.R. supervised the overall project and management and prepared the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Sheng Wang or Daniel Wacker or Bryan L. Roth.

Reviewer Information Nature thanks D. Sibley and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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