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Neurotransmitter and psychostimulant recognition by the dopamine transporter

Author

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  • Kevin H. Wang

    (Vollum Institute, Oregon Health & Science University
    †Present addresses: Amgen, Division of Molecular Structure and Characterization, Cambridge, Massachusetts 02142, USA (K.H.W.) and Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India (A.P.))

  • Aravind Penmatsa

    (Vollum Institute, Oregon Health & Science University
    †Present addresses: Amgen, Division of Molecular Structure and Characterization, Cambridge, Massachusetts 02142, USA (K.H.W.) and Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India (A.P.))

  • Eric Gouaux

    (Vollum Institute, Oregon Health & Science University
    Howard Hughes Medical Institute, Oregon Health & Science University)

Abstract

Na+/Cl–-coupled biogenic amine transporters are the primary targets of therapeutic and abused drugs, ranging from antidepressants to the psychostimulants cocaine and amphetamines, and to their cognate substrates. Here we determine X-ray crystal structures of the Drosophila melanogaster dopamine transporter (dDAT) bound to its substrate dopamine, a substrate analogue 3,4-dichlorophenethylamine, the psychostimulants d-amphetamine and methamphetamine, or to cocaine and cocaine analogues. All ligands bind to the central binding site, located approximately halfway across the membrane bilayer, in close proximity to bound sodium and chloride ions. The central binding site recognizes three chemically distinct classes of ligands via conformational changes that accommodate varying sizes and shapes, thus illustrating molecular principles that distinguish substrates from inhibitors in biogenic amine transporters.

Suggested Citation

  • Kevin H. Wang & Aravind Penmatsa & Eric Gouaux, 2015. "Neurotransmitter and psychostimulant recognition by the dopamine transporter," Nature, Nature, vol. 521(7552), pages 322-327, May.
    • Handle: RePEc:nat:nature:v:521:y:2015:i:7552:d:10.1038_nature14431
    DOI: 10.1038/nature14431
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    Cited by:

    1. Ralph Gradisch & Katharina Schlögl & Erika Lazzarin & Marco Niello & Julian Maier & Felix P. Mayer & Leticia Alves da Silva & Sophie M. C. Skopec & Randy D. Blakely & Harald H. Sitte & Marko D. Mihovi, 2024. "Ligand coupling mechanism of the human serotonin transporter differentiates substrates from inhibitors," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Sarah B Robinson & Osama Refai & J Andrew Hardaway & Sarah Sturgeon & Tessa Popay & Daniel P Bermingham & Phyllis Freeman & Jane Wright & Randy D Blakely, 2019. "Dopamine-dependent, swimming-induced paralysis arises as a consequence of loss of function mutations in the RUNX transcription factor RNT-1," PLOS ONE, Public Library of Science, vol. 14(5), pages 1-21, May.
    3. Solveig G. Schmidt & Mette Galsgaard Malle & Anne Kathrine Nielsen & Søren S.-R. Bohr & Ciara F. Pugh & Jeppe C. Nielsen & Ida H. Poulsen & Kasper D. Rand & Nikos S. Hatzakis & Claus J. Loland, 2022. "The dopamine transporter antiports potassium to increase the uptake of dopamine," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    4. Talia Zeppelin & Lucy Kate Ladefoged & Steffen Sinning & Xavier Periole & Birgit Schiøtt, 2018. "A direct interaction of cholesterol with the dopamine transporter prevents its out-to-inward transition," PLOS Computational Biology, Public Library of Science, vol. 14(1), pages 1-24, January.

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