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 DOI | 10.2210/pdb8vby/pdb |
EMDB information | 43128 |
Descriptor | Sodium-dependent dopamine transporter, SODIUM ION, DODECANE, ... (14 entities in total) |
Functional Keywords | transport, membrane, inhibitor, membrane protein |
Biological source | Homo sapiens (human) |
Total number of polymer chains | 1 |
Total formula weight | 70286.05 |
Authors | Srivastava, D.K.,Gouaux, E. (deposition date: 2023-12-12, release date: 2024-08-07, Last modification date: 2024-10-23) |
Primary citation | Srivastava, 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: 39112705DOI: 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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