X-ray structure of dopamine transporter elucidates antidepressant mechanism.
X-ray structure of dopamine transporter elucidates antidepressant mechanism.
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作者：
针对钠/氯−偶联神经递质摄取的抗抑郁药物是治疗临床抑郁症和神经病理性疼痛的主要治疗策略。然而，确定这些转运抑制剂的药理活性背后的分子相互作用，从而确定这些抑制剂导致突触神经递质水平增加的机制已被证明是难以捉摸的。在这里，我们介绍了果蝇黑腹果蝇多巴胺转运蛋白(DDAT)的晶体结构，它与三环抗抑郁药去甲替林结合，分辨率为3.0？转运蛋白被锁定在向外开放的构象中，去甲替林嵌在TMs1/6和3/8之间，阻止转运蛋白与底物结合，并阻止转运蛋白异构化为内向构象。虽然dDAT的整体结构与其原核相对Leut相似，但有多种区别，包括TM12在膜双层中途有一个扭结，覆盖细胞质门的C端螺旋，以及嵌在由TM 1a、5和7形成的沟槽中的胆固醇分子。综上所述，dDAT结构揭示了抗抑郁作用于钠偶联神经递质转运体的分子基础，阐明了真核转运体结构的关键元件和脂质的调节，从而扩大了我们对化学突触神经递质摄取的机制和调控的理解。
Antidepressants targeting Na+/Cl−-coupled neurotransmitter uptake define a major 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 (dDAT) at 3.0 Å resolution bound to the tricyclic antidepressant nortriptyline. The transporter is locked in an outward-open conformation with nortriptyline wedged between TMs1/6 and 3/8, blocking the transporter from binding substrate and from isomerizing to an inward facing conformation. While the overall structure of dDAT is similar to that of its prokaryotic relative LeuT, there are multiple distinctions that include a kink in TM12 halfway across the membrane bilayer, a latch-like C-terminal helix that caps the cytoplasmic gate, and a cholesterol molecule wedged within a groove formed by TMs 1a, 5 and 7. Taken together, the dDAT structure reveals the molecular basis for antidepressant action on sodium-coupled neurotransmitter symporters and illuminates critical elements of eukaryotic transporter structure and modulation by lipids, thus expanding our understanding of mechanism and regulation of neurotransmitter uptake at chemical synapses.
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影响因子：
25
作者：
Holton, KL;Loder, MK;Melikian, HE
通讯作者：
Melikian, HE
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1073/pnas.89.16.7782
发表时间：
1992-08-15
影响因子：
11.1
作者：
KITAYAMA, S;SHIMADA, S;UHL, GR
通讯作者：
UHL, GR
DOI：
10.1107/s0907444909042073
发表时间：
2010-01
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Chen VB;Arendall WB 3rd;Headd JJ;Keedy DA;Immormino RM;Kapral GJ;Murray LW;Richardson JS;Richardson DC
通讯作者：
Richardson DC
影响因子：
1.6
作者：
Dukkipati, Abhirarn;Park, Hyun Ho;Garcia, K. Christopher
通讯作者：
Garcia, K. Christopher