4M48

X-ray structure of dopamine transporter elucidates antidepressant mechanism

4M48 の概要

• エントリーDOI: 10.2210/pdb4m48/pdb
• 分子名称: Transporter, 9D5 antibody, light chain, 9D5 antibody, heavy chain, ... (8 entities in total)
• 機能のキーワード: slc6, neurotransmitter transporter, transport protein
• 由来する生物種: Drosophila melanogaster (Fruit fly); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 113432.93

構造登録者

Gouaux, E.,Penmatsa, A.,Wang, K. (登録日: 2013-08-06, 公開日: 2013-09-18, 最終更新日: 2024-11-06)

主引用文献

Penmatsa, A.,Wang, K.H.,Gouaux, E.
X-ray structure of dopamine transporter elucidates antidepressant mechanism.
Nature, 503:85-90, 2013

PubMed Abstract: Antidepressants targeting Na(+)/Cl(-)-coupled neurotransmitter uptake define a key therapeutic strategy to treat clinical depression and neuropathic pain. However, identifying the molecular interactions that underlie the pharmacological activity of these transport inhibitors, and thus the mechanism by which the inhibitors lead to increased synaptic neurotransmitter levels, has proven elusive. Here we present the crystal structure of the Drosophila melanogaster dopamine transporter at 3.0 Å resolution bound to the tricyclic antidepressant nortriptyline. The transporter is locked in an outward-open conformation with nortriptyline wedged between transmembrane helices 1, 3, 6 and 8, blocking the transporter from binding substrate and from isomerizing to an inward-facing conformation. Although the overall structure of the dopamine transporter is similar to that of its prokaryotic relative LeuT, there are multiple distinctions, including a kink in transmembrane helix 12 halfway across the membrane bilayer, a latch-like carboxy-terminal helix that caps the cytoplasmic gate, and a cholesterol molecule wedged within a groove formed by transmembrane helices 1a, 5 and 7. Taken together, the dopamine transporter structure reveals the molecular basis for antidepressant action on sodium-coupled neurotransmitter symporters and elucidates critical elements of eukaryotic transporter structure and modulation by lipids, thus expanding our understanding of the mechanism and regulation of neurotransmitter uptake at chemical synapses.

PubMed: 24037379
DOI: 10.1038/nature12533

実験手法

X-RAY DIFFRACTION (2.955 Å)