University Grenoble Alpes, CNRS, CEA, IBS, Grenoble, France.
Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
Nat Struct Mol Biol. 2024 Aug;31(8):1232-1242. doi: 10.1038/s41594-024-01282-x. Epub 2024 May 2.
Vortioxetine (VTX) is a recently approved antidepressant that targets a variety of serotonin receptors. Here, we investigate the drug's molecular mechanism of operation at the serotonin 5-HT receptor (5-HTR), which features two properties: VTX acts differently on rodent and human 5-HTR, and VTX appears to suppress any subsequent response to agonists. Using a combination of cryo-EM, electrophysiology, voltage-clamp fluorometry and molecular dynamics, we show that VTX stabilizes a resting inhibited state of the mouse 5-HTR and an agonist-bound-like state of human 5-HTR, in line with the functional profile of the drug. We report four human 5-HTR structures and show that the human receptor transmembrane domain is intrinsically fragile. We also explain the lack of recovery after VTX administration via a membrane partition mechanism.
文拉法辛（VTX）是一种最近被批准的抗抑郁药，它针对多种 5-羟色胺受体。在这里，我们研究了该药物在 5-羟色胺 5-HT 受体（5-HTR）上的分子作用机制，该受体具有两个特性：VTX 对啮齿动物和人类 5-HTR 的作用不同，VTX 似乎抑制了对激动剂的任何后续反应。我们使用冷冻电镜、电生理学、电压钳荧光法和分子动力学相结合的方法，表明 VTX 稳定了小鼠 5-HTR 的静止抑制状态和人类 5-HTR 的激动剂结合样状态，与药物的功能特征一致。我们报告了四个人类 5-HTR 结构，并表明人类受体跨膜结构域本质上是脆弱的。我们还通过膜分区机制解释了 VTX 给药后缺乏恢复的原因。
