X-ray structures of Drosophila dopamine transporter in complex with nisoxetine and reboxetine.
X-ray structures of Drosophila dopamine transporter in complex with nisoxetine and reboxetine.
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DOI：
10.1038/nsmb.3029
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发表时间：
2015-06
影响因子：
16.8
通讯作者：
Gouaux E
中科院分区：
文献类型：
--
作者：
Penmatsa A;Wang KH;Gouaux E
大多数抗抑郁药是通过选择性阻断Na+−、Cl、−偶联的神经递质转运体而产生疗效的。在这里，我们报告了果蝇黑腹果蝇多巴胺转运体与多环抗抑郁药尼索西汀或瑞波西汀的复合体的X射线结构。这些抑制剂通过占据底物结合部位，将转运蛋白稳定在向外开放的构象中。这些结构解释了抗抑郁药芳环上的结合口袋和取代基之间的相互作用如何调节药物转运体的选择性。
Most antidepressants elicit their therapeutic benefits through selective blockade of Na+−Cl− - coupled neurotransmitters transporters. Here we report x-ray structures of the Drosophila melanogaster dopamine transporter in complexes with the polycyclic antidepressants nisoxetine or reboxetine. The inhibitors stabilize the transporter in an outward-open conformation by occupying the substrate binding site. These structures explain how interactions between the binding pocket and substituents on the aromatic rings of antidepressants modulate drug – transporter selectivity.