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

Abstract

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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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.

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Affiliations

  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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Contributions

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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https://doi.org/10.1038/nature25758

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