Mechanism of Paroxetine (Paxil) Inhibition of the Serotonin Transporter.
Mechanism of Paroxetine (Paxil) Inhibition of the Serotonin Transporter.
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DOI：
10.1038/srep23789
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发表时间：
2016-04-01
影响因子：
4.6
通讯作者：
Singh SK
中科院分区：
文献类型：
--
作者：
Davis BA;Nagarajan A;Forrest LR;Singh SK
血清素转运蛋白 (SERT) 是一种完整的膜蛋白，它利用预先存在的钠离子、氯离子和钾离子梯度来催化突触血清素进入突触前神经元的热力学不利运动。 SERT 引起了临床的广泛关注，部分原因是它是多种精神活性药物的作用靶点，包括抗抑郁药帕罗西汀 (Paxil)，这是已知最有效的选择性血清素再摄取抑制剂。然而，SERT 中帕罗西汀的结合位点和方向仍然存在争议。为了提供分子洞察，我们基于果蝇多巴胺转运蛋白构建了 SERT 同源模型，并将帕罗西汀对接到这些模型。我们结合放射性配体结合和通量测定对野生型和突变型 SERT 测试了预测的结合构型。我们的数据表明，SERT 底物结合位点中帕罗西汀（特别是其氟苯环）的方向直接取决于该口袋的电荷分布，从而为理解和增强高亲和力抗抑郁活性提供了一条途径。
The serotonin transporter (SERT) is an integral membrane protein that exploits preexisting sodium-, chloride-, and potassium ion gradients to catalyze the thermodynamically unfavorable movement of synaptic serotonin into the presynaptic neuron. SERT has garnered significant clinical attention partly because it is the target of multiple psychoactive agents, including the antidepressant paroxetine (Paxil), the most potent selective serotonin reuptake inhibitor known. However, the binding site and orientation of paroxetine in SERT remain controversial. To provide molecular insight, we constructed SERT homology models based on the Drosophila melanogaster dopamine transporter and docked paroxetine to these models. We tested the predicted binding configurations with a combination of radioligand binding and flux assays on wild-type and mutant SERTs. Our data suggest that the orientation of paroxetine, specifically its fluorophenyl ring, in SERT’s substrate binding site directly depends on this pocket’s charge distribution, and thereby provide an avenue toward understanding and enhancing high-affinity antidepressant activity.