Abstract
The dopamine transporter (DAT) is crucial for regulating dopamine signalling and is the prime mediator for the rewarding and addictive effects of cocaine1. As part of the neurotransmitter sodium symporter family, DAT uses the Na+ gradient across cell membranes to transport dopamine against its chemical gradient2. The transport mechanism involves both intra- and extracellular gates that control substrate access to a central site. However, the molecular intricacies of this process and the inhibitory mechanism of cocaine have remained unclear. Here, we present the molecular structure of human DAT in complex with cocaine at a resolution of 2.66 Å. Our findings reveal that DAT adopts the expected LeuT-fold, posing in an outward-open conformation with cocaine bound at the central (S1) site. Notably, while an Na+ occupies the second Na+ site (Na2), the Na1 site seems to be vacant, with the side chain of Asn82 occupying the presumed Na+ space. This structural insight elucidates the mechanism for the cocaine inhibition of human DAT and deepens our understanding of neurotransmitter transport. By shedding light on the molecular underpinnings of how cocaine acts, our study lays a foundation for the development of targeted medications to combat addiction.
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Data availability
The cryo-EM reconstruction has been deposited in the Protein Data Bank under the accession code 9EO4 and the corresponding EM map has been deposited in the Electron Microscopy Data Bank under the accession code EMD-19845. All plotted data for the pharmacological experiments are available as Source data. All molecular-dynamics simulations data are available from Zenodo at https://doi.org/10.5281/zenodo.10804003 (ref. 78). A reporting summary is available as Supplementary Information. All data, as well as the associated metadata, that support the findings in this study are also available on request from the corresponding author. Source data are provided with this paper.
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Acknowledgements
We thank L. Rosenquist for technical assistance and A. Nygaard and M. Gram for critical reading of the manuscript. The financial support for this work was provided by the Lundbeck Foundation (R344-2020-1020 to C.J.L. and R368-2021-522 to A.S.); the Independent Research Fund Denmark (3101-00381B to C.J.L.); the Carlsberg Foundation (CF20-0345 to C.J.L.); and the Maersk Foundation (L-2022-00324 to J.C.N. and L-2021-00122 to K.S.). I.E.K is the recipient of a H2020 Marie Sklodowska-Curie training network (Program number 860954). A.S. was supported by a Lundbeck Foundation Fellows grant (R368-2021-522). Cryo-EM data collection was performed at the Danish Cryo-EM Facility at the Core Facility for Integrated Microscopy (CFIM), University of Copenhagen supported by the Novo Nordisk Foundation (grants NNF17SA0024386 and NNF22OC0075808).
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The study was conceptualized and designed by J.C.N., K.S. and C.J.L. J.C.N. and K.S. performed all experiments with assistance from S.B. T.P. assisted with cryo-EM grid preparation and performed the cryo-EM data collection with J.C.N. I.E.K. did the computational analysis and the molecular-dynamics simulation of the hDAT structure. Data were analysed and interpreted by J.C.N., K.S. and C.J.L. with support from A.S., T.P. and I.E.K. The manuscript was written by J.C.N. and C.J.L. with important contributions from K.S. and I.E.K. All authors read and commented on the manuscript.
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Extended data figures and tables
Extended Data Fig. 1 Purification procedure of hDATTwin.
a, Left: Coomassie stained SDS-PAGE gel (Supplementary Fig. 1) of samples taking throughout purification steps performed as described in methods. Right: Western blot (Supplementary Fig. 2) performed on SDS-PAGE gel loaded with the same samples as in Coomassie stained to track hDATTwin during purification. The gel was blotted using the monoclonal hDAT antibody MAB369 as primary antibody. b, Left: representative size-exclusion chromatography (SEC) of hDAT:cocaine on a Cytiva Superose-6 10/300 Increase column equilibrated in SEC buffer, tracking absorbance at 280 nm. Light blue shading: 14 fractions taken for SDS-PAGE (Supplementary Fig. 3) and coomassie (right). Dark blue shading: The four fractions (F46-49) taken for grid preparation. c, [3H]dopamine uptake inhibition by dopamine (homologous competition) in COS7 cells transfected with hDATWT (blue) or hDATTwin (purple) (Km = 917 [801; 1050] and 1020 [919; 1132] nM, respectively). The values are not significantly different (P = 0.554, two-sided Welch’s unpaired T-test). Data are shown as individual data points, n = 3 (hDATTwin) and n = 6 (hDATWT) biological replicates, performed in three technical replicates. Curves are fitted to the average of the data points. d, Affinities for dopamine, cocaine and MFZ 2-12 determined by competitive inhibition of either [3H]dopamine uptake or [3H]MFZ 2-12 binding for hDAT either expressed in COS7 cells, in detergent micelles or reconstituted into liposomes. Kd and Ki values are derived from the obtained IC50 values using the Cheng-Prusoff equation. Values are derived from Figs. 1d, 2b. Experiments in COS7 cells were performed using transiently expressing hDATWT. Experiments performed on purified hDATTwin in micelles were made using the scintillation proximity assay. hDATTwin was reconstituted into liposomes and [3H]dopamine transport was measured in singlets. Data are shown as mean [SEM interval].
Extended Data Fig. 2 Cryo-EM reconstruction of full-length human DAT in complex with cocaine.
Schematic representation of Cryo-EM processing workflow for hDATTwin:cocaine, showing representative micrograph and 2D classes. All steps were performed in CryoSPARC 4.4.1.
Extended Data Fig. 3 Atomic model of hDATTwin.
a, EM density of all resolved hDATTwin TMs shown as black mesh. Fitted model shown as blue ribbon and side chains displayed as sticks. Sulfur, oxygen and nitrogen atoms are colored yellow, red, and dark blue, respectively. b, GS-FSC plot showing average map resolution of 2.6 Å. c, angular sampling of the final reconstruction.
Extended Data Fig. 4 MD simulation of the non-resolved EL2 sequence.
a, Root Mean Square Fluncuation (RMSF) of EL2’s Cα atoms (amino acid residues 170-213) as a function of EL2 residues, in the last 30 ns of seven unbiased independent repeats (Supplementary Table 1). RMSF was calculated using the gmx rmsf tool using Gromacs 2021.4. b, Visual representations as ribbons, of the side view of hDAT in the last snapshots of the seven unbiased MD simulations in a zoomed-out (left) and zoomed-in view (right panel). EL2 is colored according to the MD repeat and the rest structure is colored grey in all repeats. Structures were superimposed according to the Cα atoms of their TM helices. c, Structures in panel B visualized from a top view. On the left, hDAT is depicted with both the EL2 and the rest of the structure, while on the right hDAT EL2 is depicted only for visual clarification. d, Root Mean Square Deviation (RMSD) of EL2’s Cα-atoms (amino acid residues 170-213) as a function of time, in the duration of the seven independent repeats (repeats colored mauve, blue and green). RMSD was calculated using the gmx rms tool using Gromacs 2021.4.
Extended Data Fig. 5 The c-terminus of the hDATTwin:cocaine complex is fully resolved.
a, EM density of the c-terminal domain of hDATTwin shown as black mesh with fitted structure as blue ribbon. Hydrophobic and hydrophilic residues of the amphipathic helix are shown as yellow and aqua sticks, respectively. Nitrogen, oxygen, and hydrogen atoms are shown in dark blue, red and white, respectively. b, The amphipathic c-terminal helix of hDATTwin:cocaine complex (blue) shown in colors representing hydrophobic (yellow) and hydrophilic (aqua) residues. The detergent micelle is shaded in gray with the outline marked with a solid black line. Below: a schematic representation of the helix demarcating the hydrophobic and hydrophilic sides with dashed lines in yellow and aqua, respectively.
Extended Data Fig. 6 Cocaine binding to purified hDATTwin is similar to hDAT expressed in COS7 cells.
a, Inhibition of [3H]MFZ 2-12 binding by cocaine, determined in both intact COS7 cells expressing hDATWT (blue) and in detergent solubilized hDATTwin (purple). The affinity (Ki) determined for cocaine is similar in both systems (Extended Data Fig. 1d). Data are shown as individual data points, n = 3 (detergent solubilized hDATTwin) and n = 4 (hDATTwin expressed in COS7 cells) biological replicates, performed in three technical replicates. Curves are fitted to the average of the data points. b, To the left, the obtained cryo-EM density of the hDATTwin:cocaine complex contoured at 12σ and colored according to local resolution. In the middle, a cut through of the density exposing a non-proteinaceous density, marked by a dashed box, to which R-cocaine was fitted (shown to the right). c, Diagram showing the type of interactions between the functional groups of cocaine and involved hDATTwin residues (diagram calculated and generated by Maestro, Schrodinger suite). Residues within 6 Å distance are shown as teardrops, with the pointy edge representing side chain directionality. The backbone is represented as a black line connecting residues. Residues of the sequence not within the 6 Å distance are shown as black dots. Residues that do not have a line drawn for an interaction are involved in nonspecific hydrophobic interactions with cocaine. The binding pocket is represented by a line around the ligand, colored according to the nearest protein residue’s property. Solvent exposed areas are indicated on the ligand atoms, and by the break in the line drawn around the pocket.
Extended Data Fig. 7 MD simulations of ion binding in hDATTwin.
Minimum distance measurement of ions from (a) Cl- or (b) Na2 binding sites, as a function of time, during seven independent repeats of 200 to 300 ns MD simulations of hDAT:cocaine complex. a, Cl- dissociates within the first 30 ns when distance to OH of Ser357 changes from ~0.5 nm to ~3 nm (Supplementary Video 1). Inset: enlargement of the first 30 ns simulation illustrating Cl- dissociation to the media in the 7 trajectories. b, Na+ is stably bound throughout the simulations with no significant distance change to the O- of Asp421. Calculations were performed by using the gmx mindist tool (Gromacs 2021.4) and plots were generated using GraphPad Prism V10. Each independent repeat is depicted with a different color.
Supplementary information
Supplementary Information
This file contains Supplementary Table 1 and Supplementary Figs. 1–8, including source gels and western blots.
Supplementary Checklist
Reliability and reproducibility checklist for molecular dynamics simulations.
Supplementary Video 1
Bound Cl− ion displacement during the atomistic molecular dynamics simulations. Video of a molecular dynamics simulation trajectory of 200 ns duration showing hDAT in pink ribbons, with water molecules white and red sticks, Cl− as a blue sphere and Na+ as a magenta sphere. The video shows an example of the Cl– release events taking place owing to the low stability of the chloride ion. S357 is shown in cyan, and the conformational change is followed by Cl− displacement.
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Nielsen, J.C., Salomon, K., Kalenderoglou, I.E. et al. Structure of the human dopamine transporter in complex with cocaine. Nature 632, 678–685 (2024). https://doi.org/10.1038/s41586-024-07804-3
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DOI: https://doi.org/10.1038/s41586-024-07804-3
