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-Structure paper
タイトル | Structure of the human dopamine transporter and mechanisms of inhibition. |
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ジャーナル・号・ページ | Nature, Vol. 632, Issue 8025, Page 672-677, Year 2024 |
掲載日 | 2024年8月7日 |
著者 | Dushyant Kumar Srivastava / Vikas Navratna / Dilip K Tosh / Audrey Chinn / Md Fulbabu Sk / Emad Tajkhorshid / Kenneth A Jacobson / Eric Gouaux / |
PubMed 要旨 | 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. |
リンク | Nature / PubMed:39112705 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.19 Å |
構造データ | EMDB-43128, PDB-8vby: |
化合物 | 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: |
由来 |
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キーワード | MEMBRANE PROTEIN / Transport / Membrane / Inhibitor |