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Title | Structure of the human dopamine transporter and mechanisms of inhibition. |
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Journal, issue, pages | Nature, Vol. 632, Issue 8025, Page 672-677, Year 2024 |
Publish date | Aug 7, 2024 |
![]() | Dushyant Kumar Srivastava / Vikas Navratna / Dilip K Tosh / Audrey Chinn / Md Fulbabu Sk / Emad Tajkhorshid / Kenneth A Jacobson / Eric Gouaux / ![]() |
PubMed Abstract | The neurotransmitter dopamine has central roles in mood, appetite, arousal and movement. Despite its importance in brain physiology and function, and as a target for illicit and therapeutic drugs, ...The neurotransmitter dopamine has central roles in mood, appetite, arousal and movement. 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 Zn 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)tropane (β-CFT), the non-competitive inhibitor MRS7292 and Zn (ref. ). 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 Zn ion further stabilizes the outward-facing conformation by coupling EL4 to EL2, TM7 and TM8, thus providing specific insights into how Zn restrains the movement of EL4 relative to EL2 and inhibits transport activity. |
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Methods | EM (single particle) |
Resolution | 3.19 Å |
Structure data | EMDB-43128, PDB-8vby: |
Chemicals | ![]() ChemComp-42L: ![]() PDB-1aaf: ![]() ChemComp-NAG: ![]() ChemComp-Y01: ![]() ChemComp-D10: ![]() ChemComp-LNK: ![]() ChemComp-HP6: ![]() ChemComp-ZN: ![]() ChemComp-NA: ![]() ChemComp-D12: ![]() ChemComp-MYS: ![]() ChemComp-OCT: ![]() ChemComp-HOH: |
Source |
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![]() | MEMBRANE PROTEIN / Transport / Membrane / Inhibitor |