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X-ray structures of Drosophila dopamine transporter in complex with nisoxetine and reboxetine


Most antidepressants elicit their therapeutic benefits through selective blockade of Na+/Cl-coupled neurotransmitter transporters. Here we report X-ray structures of the Drosophila melanogaster dopamine transporter in complexes with the polycyclic antidepressants nisoxetine or reboxetine. The inhibitors stabilize the transporter in an outward-open conformation by occupying the substrate-binding site. These structures explain how interactions between the binding pocket and substituents on the aromatic rings of antidepressants modulate drug-transporter selectivity.

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Figure 1: Critical interactions for antidepressant recognition in the binding pocket of dDAT.
Figure 2: Comparison of ligand orientations in antidepressant-bound dDAT structures and predicted interactions in hNET and hDAT.

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  1. 1

    Torres, G.E., Gainetdinov, R.R. & Caron, M.G. Nat. Rev. Neurosci. 4, 13–25 (2003).

    CAS  Article  Google Scholar 

  2. 2

    Rudnick, G. Methods Enzymol. 296, 233–247 (1998).

    CAS  Article  Google Scholar 

  3. 3

    Kristensen, A.S. et al. Pharmacol. Rev. 63, 585–640 (2011).

    CAS  Article  Google Scholar 

  4. 4

    Glowinski, J. & Axelrod, J. Nature 204, 1318–1319 (1964).

    CAS  Article  Google Scholar 

  5. 5

    Stahl, S.M. J. Clin. Psychiatry 59, 5–14 (1998).

    CAS  PubMed  Google Scholar 

  6. 6

    Iversen, L. Br. J. Pharmacol. 147, S82–S88 (2006).

    CAS  Article  Google Scholar 

  7. 7

    Pörzgen, P. et al. Mol. Pharmacol. 59, 83–95 (2001).

    Article  Google Scholar 

  8. 8

    Penmatsa, A., Wang, K.H. & Gouaux, E. Nature 503, 85–90 (2013).

    CAS  Article  Google Scholar 

  9. 9

    Singh, S.K., Yamashita, A. & Gouaux, E. Nature 448, 952–956 (2007).

    CAS  Article  Google Scholar 

  10. 10

    Lemberger, L., Terman, S., Rowe, H. & Billings, R. Br. J. Clin. Pharmacol. 3, 215–220 (1976).

    CAS  Article  Google Scholar 

  11. 11

    Wong, E.H. et al. Biol. Psychiatry 47, 818–829 (2000).

    CAS  Article  Google Scholar 

  12. 12

    Wang, K.H., Penmatsa, A. & Gouaux, E. Nature doi:10.1038/nature14431 (11 May 2015).

  13. 13

    Piscitelli, C.L., Krishnamurthy, H. & Gouaux, E. Nature 468, 1129–1132 (2010).

    CAS  Article  Google Scholar 

  14. 14

    Sørensen, L. et al. J. Biol. Chem. 287, 43694–43707 (2012).

    Article  Google Scholar 

  15. 15

    Wang, H. et al. Nature 503, 141–145 (2013).

    CAS  Article  Google Scholar 

  16. 16

    Richelson, E. & Pfenning, M. Eur. J. Pharmacol. 104, 277–286 (1984).

    CAS  Article  Google Scholar 

  17. 17

    Zhou, J. Drugs Future 29, 1235–1244 (2004).

    CAS  Article  Google Scholar 

  18. 18

    Gehlert, D.R., Schober, D.A. & Gackenheimer, S.L. J. Neurochem. 64, 2792–2800 (1995).

    CAS  Article  Google Scholar 

  19. 19

    Fleishaker, J.C. Clin. Pharmacokinet. 39, 413–427 (2000).

    CAS  Article  Google Scholar 

  20. 20

    Benson, N. et al. Br. J. Pharmacol. 160, 389–398 (2010).

    CAS  Article  Google Scholar 

  21. 21

    Reeves, P.J., Callewaert, N., Contreras, R. & Khorana, H.G. Proc. Natl. Acad. Sci. USA 99, 13419–13424 (2002).

    CAS  Article  Google Scholar 

  22. 22

    Goehring, A. et al. Nat. Protoc. 9, 2574–2585 (2014).

    CAS  Article  Google Scholar 

  23. 23

    Otwinowski, Z. & Minor, W. Methods Enzymol. 276, 307–326 (1997).

    CAS  Article  Google Scholar 

  24. 24

    Kabsch, W. Acta Crystallogr. D Biol. Crystallogr. 66, 125–132 (2010).

    CAS  Article  Google Scholar 

  25. 25

    McCoy, A.J. et al. J. Appl. Crystallogr. 40, 658–674 (2007).

    CAS  Article  Google Scholar 

  26. 26

    Afonine, P.V. et al. Acta Crystallogr. D Biol. Crystallogr. 68, 352–367 (2012).

    CAS  Article  Google Scholar 

  27. 27

    Emsley, P. & Cowtan, K. Acta Crystallogr. D Biol. Crystallogr. 60, 2126–2132 (2004).

    Article  Google Scholar 

  28. 28

    Schwede, T., Kopp, J., Guex, N. & Peitsch, M.C. Nucleic Acids Res. 31, 3381–3385 (2003).

    CAS  Article  Google Scholar 

  29. 29

    Pei, J., Kim, B.H. & Grishin, N.V. Nucleic Acids Res. 36, 2295–2300 (2008).

    CAS  Article  Google Scholar 

  30. 30

    Quick, M. & Javitch, J.A. Proc. Natl. Acad. Sci. USA 104, 3603–3608 (2007).

    CAS  Article  Google Scholar 

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We thank J. Coleman and other members of the Gouaux laboratory for helpful discussions, L. Vaskalis for assistance with figures and H. Owen for help with manuscript preparation. We acknowledge the staff of the Northeastern Collaborative Access Team at the Advanced Photon Source for assistance with data collection. This work was supported by a US National Institutes of Health Mental Health (NIH-MH) R. Kirschstein postdoctoral fellowship and a Brain and Behavior Research Foundation Young Investigator research award (K.H.W.); by a postdoctoral fellowship from the American Heart Association (A.P.); by the NIH-MH (E.G.); and by the Methamphetamine Abuse Research Center of the Oregon Health & Science University (P50DA018165 to E.G.). E.G. is supported as an investigator with the Howard Hughes Medical Institute.

Author information




A.P., K.H.W. and E.G. designed the project. A.P. and K.H.W. performed protein purification, crystallography and biochemical assays. A.P., K.H.W. and E.G. wrote the manuscript.

Corresponding author

Correspondence to Eric Gouaux.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 FoFc densities for ligands complexed with dDAT.

a, Nisoxetine (2.2 σ); b, reboxetine (2.4 s); Cyan sticks represent (S)-stereoisomer whereas magenta sticks are (R)-stereoisomer for both the drugs.

Supplementary information

Supplementary Text and Figures

Supplementary Figure 1 and Supplementary Tables 1 and 2 (PDF 310 kb)

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Penmatsa, A., Wang, K. & Gouaux, E. X-ray structures of Drosophila dopamine transporter in complex with nisoxetine and reboxetine. Nat Struct Mol Biol 22, 506–508 (2015).

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