Structure of the human dopamine transporter and mechanisms of inhibition

  • Nature. 2024 Aug;632(8025):672-677. doi: 10.1038/s41586-024-07739-9.
Dushyant Kumar Srivastava  1 ,  Vikas Navratna  1  2 ,  Dilip K Tosh  3 ,  Audrey Chinn  1 ,  Md Fulbabu Sk  4  5  6 ,  Emad Tajkhorshid  4  5  6 ,  Kenneth A Jacobson  7 ,  Eric Gouaux  8  9
Affiliations
  • 1. Vollum Institute, Oregon Health and Science University, Portland, OR, USA.
  • 2. Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
  • 3. Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
  • 4. Theoretical and Computational Biophysics Group, NIH Center for Macromolecular Modeling and Visualization, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • 5. Department of Biochemistry University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • 6. Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • 7. Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA. [email protected].
  • 8. Vollum Institute, Oregon Health and Science University, Portland, OR, USA. [email protected].
  • 9. Howard Hughes Medical Institute, Oregon Health and Science University, Portland, OR, USA. [email protected].
PMID: 39112705 DOI: 10.1038/s41586-024-07739-9
Abstract

The neurotransmitter dopamine has central roles in mood, appetite, arousal and movement1. Despite its importance in brain physiology and function, and as a target for illicit and therapeutic drugs, the human Dopamine Transporter (hDAT) and mechanisms by which it is inhibited by small molecules and Zn2+ are without a high-resolution structural context. Here we determine the structure of hDAT in a tripartite complex with the competitive inhibitor and cocaine analogue, (-)-2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane2 (β-CFT), the non-competitive inhibitor MRS72923 and Zn2+ (ref. 4). We show how β-CFT occupies the central site, approximately halfway across the membrane, stabilizing the transporter in an outward-open conformation. MRS7292 binds to a structurally uncharacterized allosteric site, adjacent to the extracellular vestibule, sequestered underneath the extracellular loop 4 (EL4) and adjacent to transmembrane helix 1b (TM1b), acting as a wedge, precluding movement of TM1b and closure of the extracellular gate. A Zn2+ ion further stabilizes the outward-facing conformation by coupling EL4 to EL2, TM7 and TM8, thus providing specific insights into how Zn2+ restrains the movement of EL4 relative to EL2 and inhibits transport activity.

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