top of page

Our Treatment is Based on REAL Science! ~ 50+ PUBMED: D2 Receptor Articles

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.


D2 Structure to Function
.pdf
Download PDF • 615KB

  1. 1Missale, C., Nash, S. R., Robinson, S. W., Jaber, M. & Caron, M. G. Dopamine receptors: from structure to function. Physiol. Rev. 78, 189–225 (1998) Article CAS PubMed Google Scholar

  2. 2Creese, I., Burt, D. R. & Snyder, S. H. Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 192, 481–483 (1976) Article ADS CAS PubMed Google Scholar

  3. 3Meltzer, H. Y., Matsubara, S. & Lee, J.-C. 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) CAS PubMed Google Scholar

  4. 4Roth, B. L., Sheffler, D. J. & Kroeze, W. K. Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat. Rev. Drug Discov. 3, 353–359 (2004) Article CAS PubMed Google Scholar

  5. 5Roth, B. L. Drugs and valvular heart disease. N. Engl. J. Med. 356, 6–9 (2007) Article CAS PubMed Google Scholar

  6. 6Seeman, P. & Lee, T. Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science 188, 1217–1219 (1975) Article ADS CAS PubMed PubMed Central Google Scholar

  7. 7Sibley, D. R. & Monsma, F. J. Jr. Molecular biology of dopamine receptors. Trends Pharmacol. Sci. 13, 61–69 (1992) Article CAS PubMed Google Scholar

  8. 8Beaulieu, J. M. & Gainetdinov, R. R. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol. Rev. 63, 182–217 (2011) Article CAS PubMed Google Scholar

  9. 9Volkow, N. D., Fowler, J. S., Wang, G. J., Swanson, J. M. & Telang, F. Dopamine in drug abuse and addiction: results of imaging studies and treatment implications. Arch. Neurol. 64, 1575–1579 (2007) Article PubMed Google Scholar

  10. 10Bunzow, J. R. et al. Cloning and expression of a rat D2 dopamine receptor cDNA. Nature 336, 783–787 (1988) Article ADS CAS PubMed Google Scholar

  11. 11Grandy, D. K. et al. Cloning of the cDNA and gene for a human D2 dopamine receptor. Proc. Natl Acad. Sci. USA 86, 9762–9766 (1989) Article ADS CAS PubMed Google Scholar

  12. 12Monsma, F. J., Jr, McVittie, L. D., Gerfen, C. R., Mahan, L. C. & Sibley, D. R. Multiple D2 dopamine receptors produced by alternative RNA splicing. Nature 342, 926–929 (1989) Article ADS CAS PubMed Google Scholar

  13. 13Allen, J. A. 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) Article ADS PubMed Google Scholar

  14. 14Javitch, J. A., Fu, D., Chen, J. & Karlin, A. Mapping the binding-site crevice of the dopamine D2 receptor by the substituted-cysteine accessibility method. Neuron 14, 825–831 (1995) Article CAS PubMed Google Scholar

  15. 15Ballesteros, J. A., Shi, L. & Javitch, J. A. 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) Article CAS PubMed Google Scholar

  16. 16Chien, E. Y. et al. Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist. Science 330, 1091–1095 (2010) Article ADS CAS PubMed PubMed Central Google Scholar

  17. 17Wang, S. et al. D4 dopamine receptor high-resolution structures enable the discovery of selective agonists. Science 358, 381–386 (2017) Article ADS CAS PubMed PubMed Central Google Scholar

  18. 18Manglik, A. et al. Structure-based discovery of opioid analgesics with reduced side effects. Nature 537, 185–190 (2016) Article ADS CAS PubMed PubMed Central Google Scholar

  19. 19Wacker, D., Stevens, R. C. & Roth, B. L. How ligands illuminate GPCR molecular pharmacology. Cell 170, 414–427 (2017) Article CAS PubMed PubMed Central Google Scholar

  20. 20McCorvy, J. D. et al. Structure-inspired design of β-arrestin-biased ligands for aminergic GPCRs. Nat. Chem. Biol. 14, 126–134 (2018) Article CAS PubMed Google Scholar

  21. 21Free, R. B. 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) Article CAS PubMed PubMed Central Google Scholar

  22. 22Roberts, D. J. & Strange, P. G. Mechanisms of inverse agonist action at D2 dopamine receptors. Br. J. Pharmacol. 145, 34–42 (2005) Article CAS PubMed PubMed Central Google Scholar

  23. 23Rasmussen, S. G. et al. Crystal structure of the β2 adrenergic receptor-Gs protein complex. Nature 477, 549–555 (2011) Article ADS CAS PubMed PubMed Central Google Scholar

  24. 24Shapiro, D. A., Kristiansen, K., Weiner, D. M., Kroeze, W. K. & Roth, B. L. 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) Article CAS Google Scholar

  25. 25Ballesteros, J. A. 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) Article CAS PubMed Google Scholar

  26. 26Palczewski, K. et al. Crystal structure of rhodopsin: a G protein-coupled receptor. Science 289, 739–745 (2000) Article ADS CAS PubMed Google Scholar

  27. 27Janssen, P. A. 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) CAS PubMed Google Scholar

  28. 28Kapur, S., Zipursky, R., Jones, C., Remington, G. & Houle, S. 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) Article CAS PubMed Google Scholar

  29. 29Kapur, S. & Seeman, P. Does fast dissociation from the dopamine D2 receptor explain the action of atypical antipsychotics?: A new hypothesis. Am. J. Psychiatry 158, 360–369 (2001) Article CAS PubMed Google Scholar

  30. 30Sykes, D. A. et al. Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors. Nat. Commun. 8, 763 (2017) Article ADS CAS PubMed PubMed Central Google Scholar

  31. 31Rosenbaum, D. M. et al. GPCR engineering yields high-resolution structural insights into β2-adrenergic receptor function. Science 318, 1266–1273 (2007) Article ADS CAS Google Scholar

  32. 32Caffrey, M. & Cherezov, V. Crystallizing membrane proteins using lipidic mesophases. Nat. Protocols 4, 706–731 (2009) Article CAS PubMed PubMed Central Google Scholar

  33. 33Minor, W., Cymborowski, M., Otwinowski, Z. & Chruszcz, M. 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) Article CAS PubMed Google Scholar

  34. 34McCoy, A. J. et al. Phaser crystallographic software. J. Appl. Crystallogr. 40, 658–674 (2007) CAS PubMed PubMed Central Google Scholar

  35. 35Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D Biol. Crystallogr. 66, 213–221 (2010) Article CAS PubMed PubMed Central Google Scholar

  36. 36Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D Biol. Crystallogr. 66, 486–501 (2010) Article CAS PubMed PubMed Central Google Scholar

  37. 37Motulsky, H. J. & Mahan, L. C. The kinetics of competitive radioligand binding predicted by the law of mass action. Mol. Pharmacol. 25, 1–9 (1984) CAS PubMed Google Scholar

  38. 38Pei, J. & Grishin, N. V. PROMALS3D: multiple protein sequence alignment enhanced with evolutionary and three-dimensional structural information. Methods Mol. Biol. 1079, 263–271 (2014) Article PubMed PubMed Central Google Scholar

  39. 39Webb, B. & Sali, A. Comparative protein structure modeling using MODELLER. Curr. Protoc. Bioinformatics 47, 5 6 1–5 6 32 (2014) Article Google Scholar

  40. 40Coleman, R. G., Carchia, M., Sterling, T., Irwin, J. J. & Shoichet, B. K. Ligand pose and orientational sampling in molecular docking. PLoS One 8, e75992 (2013) Article ADS CAS PubMed PubMed Central Google Scholar

  41. 41Southan, C. 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) Article CAS PubMed Google Scholar

  42. 42Mysinger, M. M., Carchia, M., Irwin, J. J. & Shoichet, B. K. Directory of useful decoys, enhanced (DUD-E): better ligands and decoys for better benchmarking. J. Med. Chem. 55, 6582–6594 (2012) Article CAS PubMed PubMed Central Google Scholar

  43. 43Case, D. A . et al. AMBER 2015. (University of California, 2015)

  44. 44Word, J. M., Lovell, S. C., Richardson, J. S. & Richardson, D. C. Asparagine and glutamine: using hydrogen atom contacts in the choice of side-chain amide orientation. J. Mol. Biol. 285, 1735–1747 (1999) Article CAS PubMed Google Scholar

  45. 45Gallagher, K. & Sharp, K. Electrostatic contributions to heat capacity changes of DNA-ligand binding. Biophys. J. 75, 769–776 (1998) Article ADS CAS PubMed PubMed Central Google Scholar

  46. 46Sharp, K. A. Polyelectrolyte electrostatics: Salt dependence, entropic, and enthalpic contributions to free energy in the nonlinear Poisson–Boltzmann model. Biopolymers 36, 227–243 (1995) Article CAS Google Scholar

  47. 47Mysinger, M. M. & Shoichet, B. K. Rapid context-dependent ligand desolvation in molecular docking. J. Chem. Inf. Model. 50, 1561–1573 (2010) Article CAS PubMed Google Scholar

  48. 48Sadowski, J., Gasteiger, J. & Klebe, G. Comparison of automatic three-dimensional model builders using 639 X-ray structures. J. Chem. Inf. Comput. Sci. 34, 1000–1008 (1994) Article CAS Google Scholar

  49. 49Hawkins, P. C., Skillman, A. G., Warren, G. L., Ellingson, B. A. & Stahl, M. T. 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) Article CAS PubMed PubMed Central Google Scholar

  50. 50Chambers, C. C., Hawkins, G. D., Cramer, C. J. & Truhlar, D. G. Model for aqueous solvation based on class IV atomic charges and first solvation shell effects. J. Phys. Chem. 100, 16385–16398 (1996) Article CAS Google Scholar

  51. 51Li, J., Zhu, T., Cramer, C. J. & Truhlar, D. G. New class IV charge model for extracting accurate partial charges from wave functions. J. Phys. Chem. A 102, 1820–1831 (1998) Article CAS Google Scholar

Acknowledgements 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.





Comments


bottom of page