Yang Dongxue, Gouaux Eric
Vollum Institute, Oregon Health and Science University, Portland, OR 97239, USA.
Howard Hughes Medical Institute, Oregon Health and Science University, Portland, OR 97239, USA.
Sci Adv. 2021 Dec 3;7(49):eabl3857. doi: 10.1126/sciadv.abl3857. Epub 2021 Dec 1.
The serotonin transporter (SERT) terminates serotonin signaling by using sodium and chloride gradients to drive reuptake of serotonin into presynaptic neurons and is the target of widely used medications to treat neuropsychiatric disorders. Despite decades of study, the molecular mechanism of serotonin transport, the coupling to ion gradients, and the role of the allosteric site have remained elusive. Here, we present cryo–electron microscopy structures of SERT in serotonin-bound and serotonin-free states, in the presence of sodium or potassium, resolving all fundamental states of the transport cycle. From the SERT-serotonin complex, we localize the substrate-bound allosteric site, formed by an aromatic pocket positioned in the scaffold domain in the extracellular vestibule, connected to the central site via a short tunnel. Together with elucidation of multiple apo state conformations, we provide previously unseen structural understanding of allosteric modulation, demonstrating how SERT binds serotonin from synaptic volumes and promotes unbinding into the presynaptic neurons.
血清素转运体（SERT）通过利用钠和氯梯度驱动血清素重新摄取到突触前神经元中来终止血清素信号传导，并且是广泛用于治疗神经精神疾病药物的靶点。尽管经过数十年的研究，血清素转运的分子机制、与离子梯度的偶联以及变构位点的作用仍然难以捉摸。在这里，我们展示了在存在钠或钾的情况下，血清素结合状态和无血清素状态下SERT的冷冻电子显微镜结构，解析了转运循环的所有基本状态。从SERT-血清素复合物中，我们定位了由位于细胞外前庭支架结构域中的芳香口袋形成的底物结合变构位点，该口袋通过一条短通道与中央位点相连。结合对多种无配体状态构象的阐明，我们提供了以前未见的变构调节结构理解，展示了SERT如何从突触间隙结合血清素并促进其释放到突触前神经元中。
