2. Academic Validation
  3. Structure of the human dopamine transporter and mechanisms of inhibition

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

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. kennethj@niddk.nih.gov.
  • 8 Vollum Institute, Oregon Health and Science University, Portland, OR, USA. gouauxe@ohsu.edu.
  • 9 Howard Hughes Medical Institute, Oregon Health and Science University, Portland, OR, USA. gouauxe@ohsu.edu.
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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