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Structure paper

TitleStructure of the human dopamine transporter and mechanisms of inhibition.
Journal, issue, pagesNature, Vol. 632, Issue 8025, Page 672-677, Year 2024
Publish dateAug 7, 2024
AuthorsDushyant Kumar Srivastava / Vikas Navratna / Dilip K Tosh / Audrey Chinn / Md Fulbabu Sk / Emad Tajkhorshid / Kenneth A Jacobson / Eric Gouaux /
PubMed AbstractThe 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.
External linksNature / PubMed:39112705 / PubMed Central
MethodsEM (single particle)
Resolution3.19 Å
Structure data

43128

8vby

EMDB-43128, PDB-8vby:
Structure of the human dopamine transporter in complex with beta-CFT, MRS7292 and divalent zinc
Method: EM (single particle) / Resolution: 3.19 Å

Chemicals

ChemComp-42L:
methyl (1R,2S,3S,5S)-3-(4-fluorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate / inhibitor*YM

PDB-1aaf:
NUCLEOCAPSID ZINC FINGERS DETECTED IN RETROVIRUSES: EXAFS STUDIES ON INTACT VIRUSES AND THE SOLUTION-STATE STRUCTURE OF THE NUCLEOCAPSID PROTEIN FROM HIV-1

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-D10:
DECANE

ChemComp-LNK:
PENTANE

ChemComp-HP6:
HEPTANE

ChemComp-ZN:
Unknown entry

ChemComp-NA:
Unknown entry

ChemComp-D12:
DODECANE

ChemComp-MYS:
PENTADECANE

ChemComp-OCT:
N-OCTANE

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Transport / Membrane / Inhibitor

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