Structure of the human dopamine transporter and mechanisms of inhibition

Dushyant Kumar Srivastava, Vikas Navratna, Dilip K. Tosh, Audrey Chinn, Md Fulbabu Sk, Emad Tajkhorshid, Kenneth A. Jacobson () and Eric Gouaux ()
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Dushyant Kumar Srivastava: Oregon Health and Science University
Vikas Navratna: Oregon Health and Science University
Dilip K. Tosh: National Institutes of Health
Audrey Chinn: Oregon Health and Science University
Md Fulbabu Sk: University of Illinois at Urbana-Champaign
Emad Tajkhorshid: University of Illinois at Urbana-Champaign
Kenneth A. Jacobson: National Institutes of Health
Eric Gouaux: Oregon Health and Science University

Nature, 2024, vol. 632, issue 8025, 672-677

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07739-9

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