State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P. R. China.
Beijing Jingtai Technology, Beijing, P. R. China.
Nature. 2024 Sep;633(8029):473-479. doi: 10.1038/s41586-024-07810-5. Epub 2024 Aug 14.
Norepinephrine transporter (NET; encoded by SLC6A2) reuptakes the majority of the released noradrenaline back to the presynaptic terminals, thereby affecting the synaptic noradrenaline level. Genetic mutations and dysregulation of NET are associated with a spectrum of neurological conditions in humans, making NET an important therapeutic target. However, the structure and mechanism of NET remain unclear. Here we provide cryogenic electron microscopy structures of the human NET (hNET) in three functional states-the apo state, and in states bound to the substrate meta-iodobenzylguanidine (MIBG) or the orthosteric inhibitor radafaxine. These structures were captured in an inward-facing conformation, with a tightly sealed extracellular gate and an open intracellular gate. The substrate MIBG binds at the centre of hNET. Radafaxine also occupies the substrate-binding site and might block the structural transition of hNET for inhibition. These structures provide insights into the mechanism of substrate recognition and orthosteric inhibition of hNET.
去甲肾上腺素转运体（NET；由 SLC6A2 编码）将大部分释放的去甲肾上腺素再摄取回突触前末梢，从而影响突触去甲肾上腺素水平。NET 的遗传突变和失调与人类一系列神经疾病有关，使其成为一个重要的治疗靶点。然而，NET 的结构和机制仍不清楚。在这里，我们提供了三种功能状态下的人去甲肾上腺素转运体（hNET）的低温电子显微镜结构——apo 状态，以及与底物间碘苄胍（MIBG）或正构抑制剂 radafaxine 结合的状态。这些结构以向内取向的构象捕获，具有紧密密封的细胞外门和开放的细胞内门。底物 MIBG 结合在 hNET 的中心。Radafaxine 也占据了底物结合位点，可能会阻止 hNET 的结构转变以进行抑制。这些结构为 hNET 的底物识别和正构抑制机制提供了见解。
