8VBY

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

これはPDB形式変換不可エントリーです。

8VBY の概要

• エントリーDOI: 10.2210/pdb8vby/pdb
• EMDBエントリー: 43128
• 分子名称: Sodium-dependent dopamine transporter, SODIUM ION, DODECANE, ... (14 entities in total)
• 機能のキーワード: transport, membrane, inhibitor, membrane protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 70286.05

構造登録者

Srivastava, D.K.,Gouaux, E. (登録日: 2023-12-12, 公開日: 2024-08-07, 最終更新日: 2024-10-23)

主引用文献

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

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

実験手法

ELECTRON MICROSCOPY (3.19 Å)