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8VBY

Structure of the human dopamine transporter in complex with beta-CFT, MRS7292 and divalent zinc

This is a non-PDB format compatible entry.
Summary for 8VBY
Entry DOI10.2210/pdb8vby/pdb
EMDB information43128
DescriptorSodium-dependent dopamine transporter, SODIUM ION, DODECANE, ... (14 entities in total)
Functional Keywordstransport, membrane, inhibitor, membrane protein
Biological sourceHomo sapiens (human)
Total number of polymer chains1
Total formula weight70286.05
Authors
Srivastava, D.K.,Gouaux, E. (deposition date: 2023-12-12, release date: 2024-08-07, Last modification date: 2024-10-23)
Primary citationSrivastava, D.K.,Navratna, V.,Tosh, D.K.,Chinn, A.,Sk, M.F.,Tajkhorshid, E.,Jacobson, K.A.,Gouaux, E.
Structure of the human dopamine transporter and mechanisms of inhibition.
Nature, 632:672-677, 2024
Cited by
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 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.
PubMed: 39112705
DOI: 10.1038/s41586-024-07739-9
PDB entries with the same primary citation
Experimental method
ELECTRON MICROSCOPY (3.19 Å)
Structure validation

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