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

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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Figure 1: Structural details of DRD2 and comparison with DRD3 and DRD4.
Figure 2: Comparison of the ligand-binding pocket across the D2-like family receptors.
Figure 3: Different extended binding pockets revealed across D2-like family receptors.
Figure 4: The hydrophobic ‘patch’ of the DRD2 binding pocket.

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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.

Author information

Authors and Affiliations

Authors

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.

Corresponding authors

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

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The authors declare no competing financial interests.

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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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Extended data figures and tables

Extended Data Figure 1 Thermostability of DRD2 constructs, crystal packing of the DRD2–risperidone complex and representative electron density of the DRD2 structure.

a, Membranes containing DRD2 or DRD2 with thermostability mutations were heated for 30 min with 1 nM [3H]-N-methylspiperone and the amount of bound [3H]-ligand was determined. b, Purified DRD2–T4L protein (with or without thermostability mutations) was heated with 10 μM risperidone and 1 μM BODIPY FL l-cystine dye using a temperature gradient and the amount of dye bound to unfolding protein was determined. Data were analysed by nonlinear regression and apparent Tm values (transition temperature where 50% of the receptor is inactive) were determined from analysis of the sigmoidal melting curves. All data in a and b are mean ± s.e.m. of three independent assays. ce, Packing of the DRD2–risperidone complex crystallized in the P212121 spacegroup. DRD2 is shown in green and the T4L-fusion protein is shown in red, or in cyan where it interacts with DRD2. EL1 and EL2 of DRD2 are shown in magenta and blue, respectively. f, 2FoFc electron density map (blue mesh) of risperidone (yellow) contoured at 1σ. g, FoFc omit map (green mesh) contoured at 3.0σ of risperidone (yellow). h, 2 FoFc electron density map of DRD2 binding pocket residues (blue mesh) contoured at 1σ.

Source data

Extended Data Figure 2 Conserved hydrophobic residue of EL2 in all available aminergic receptor structures.

In all panels, receptors are shown as cartoons. Ligands and residues are shown as sticks. a, 5HT1B (PDB code: 4IAR). b, 5HT2B (PDB code: 5TVN). c, DRD2. d, DRD3 (PDB code: 3PBL). e, DRD4 (PDB code: 5WIU). f, ACM1 (PDB code: 5CXV). g, ACM2 (PDB code: 3UON). h, ACM3 (PDB code: 4ADJ). i, ACM4 (PDB code: 4DSG). j, HRH1 (PDB code: 3RZE). k, ADRB1 (PDB code: 2VT4). l, ADRB2 (PDB code: 2RH1). m, DRD2. n, Conserved EL2 hydrophobic residues (red box) are located two residues away from a conserved cysteine that forms a disulphide bridge between EL2 and TMIII. Notable exceptions to the presence of a hydrophobic residue are DRD1 and DRD5, which contain a serine, and HRH1 and HRH4, which contain a threonine and proline, respectively.

Extended Data Figure 3 Comparison of D2 receptors viewed from the extracellular side, and structural alignment with β2AR and A2AR reveals an inactive state of DRD2.

ad, DRD2, green; DRD3, magenta (PDB code: 3PBL); DRD4, blue (PDB code: 5WIU). Risperidone (yellow), eticlopride (cyan) and nemonapride (light pink) are shown as sticks and spheres. Displacements of H6.55 and Y/V7.35 are shown at DRD2 (a), DRD3 (b) and DRD4 (c). d, Views from the extracellular side of DRD2 and DRD3. e, f, Superposition of TMVI at DRD2 (green), inactive β2AR (yellow, PDB code: 2RH1), active β2AR (light pink, PDB code: 3SN6), inactive A2AR (brown, PDB code: 3REY) and active A2AR (blue, PDB code: 5G53) aligned through helices I–IV. gj, Cytoplasmic view of alignment between DRD2 and active and inactive β2AR (g, h) or A2AR (i, j). Rearrangements of two highly conserved residues (Y7.53 and R3.50) within the core of the receptor are shown as sticks. Ligands are omitted for clarity and hydrogen bonds are shown as grey dotted lines.

Extended Data Figure 4 Conserved Trp of EL1 in all available aminergic receptor structures shows its unique position in DRD2–risperidone.

Receptors are shown as cartoons. Ligands and residues are shown as sticks. a, Conserved Trp residues of EL1 are shown in red boxes. b, 5HT1B (PDB code: 4IAR). c, 5HT2B (PDB code: 5TVN). d, DRD2. e, DRD3 (PDB code: 3PBL). f, DRD4 (PDB code: 5WIU). g, ACM1 (PDB code: 5CXV). h, ACM2 (PDB code: 3UON). i, ACM3 (PDB code: 4ADJ). j, ACM4 (PDB code: 4DSG). k, HRH1 (PDB code: 3RZE). l, ADRB1 (PDB code: 2VT4). m, ADRB2 (PDB code: 2RH1).

Extended Data Figure 5 Risperidone has distinct poses in solution and in complex with DRD2, and comparison of X-ray structure and model of DRD2.

a, Trp100EL1 determines the configuration of the tetrahydropyridopyrimidinone moiety of risperidone. Structure of unbound risperidone shown in green and DRD2-bound risperidone shown in yellow. b, Electron density (2FoFc maps, blue mesh) for W100EL1 in the DRD2–risperidone complex (contoured at 1.0σ). c, 2FoFc electron density map (blue mesh) of Leu942.64, Trp100EL1, Ile184EL2 and risperidone (yellow) contoured at 0.8σ. d, Overall view of DRD2–risperidone X-ray structure and model. eh, Comparison of X-ray structure and model of DRD2. In dh, DRD2 X-ray structure and model are shown as cartoons, with the X-ray structure in green and the model in magenta or blue. Risperidone is shown in the X-ray structure as yellow spheres or sticks, and in the model as cyan or light pink.

Extended Data Figure 6 Patch residues of the DRD2 orthosteric pocket impair the dissociation rates of risperidone, aripiprazole, N-methylspiperone and nemonapride.

ag, Comparison of risperidone dissociation from wild-type DRD2 (a) and W100EL1A (b), W100EL1L (c), W100EL1F (d), L942.64A (e), I184EL2A (f) or L942.64A/I184EL2A (g) mutants. hn, Comparison of aripiprazole dissociation from wild-type DRD2 (h) and W100EL1A (i), W100EL1L (j), W100EL1F (k), L942.64A (l), I184EL2A (m) or L942.64A/I184EL2A (n) mutants. o, p, Comparison of N-methylspiperone (o) or nemonapride (p) dissociation from wild-type DRD2 and W100EL1A, W100EL1L or W100EL1F mutants (n = 3). q, r, Comparison of N-methylspiperone (q) or nemonapride (r) dissociation from wild-type DRD2 and L942.64A, I184EL2A or L942.64A/I184EL2A mutants. All data are mean ± s.e.m. of four independent assays (n = 4 independent experiments). Error bars in or denote s.e.m. from four independent assays.

Source data

Extended Data Table 1 Affinities of antipsychotic drugs for thermostabilized mutant and wild-type DRD2
Extended Data Table 2 Data collection and refinement statistics
Extended Data Table 3 Affinity of risperidone and nemonapride for ligand-binding-pocket mutants of the D2 dopamine receptor
Extended Data Table 4 Compound dissociation and association rates on wild-type and mutant DRD2

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Wang, S., Che, T., Levit, A. et al. Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone. Nature 555, 269–273 (2018). https://doi.org/10.1038/nature25758

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