Danish Research Institute of Translational Neuroscience-DANDRITE, Nordic EMBL Partnership for Molecular Medicine, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
European Molecular Biology Laboratory, Hamburg Unit c/o DESY, Hamburg, Germany.
Nature. 2021 Mar;591(7851):677-681. doi: 10.1038/s41586-021-03274-z. Epub 2021 Mar 3.
The human glycine transporter 1 (GlyT1) regulates glycine-mediated neuronal excitation and inhibition through the sodium- and chloride-dependent reuptake of glycine. Inhibition of GlyT1 prolongs neurotransmitter signalling, and has long been a key strategy in the development of therapies for a broad range of disorders of the central nervous system, including schizophrenia and cognitive impairments. Here, using a synthetic single-domain antibody (sybody) and serial synchrotron crystallography, we have determined the structure of GlyT1 in complex with a benzoylpiperazine chemotype inhibitor at 3.4 Å resolution. We find that the inhibitor locks GlyT1 in an inward-open conformation and binds at the intracellular gate of the release pathway, overlapping with the glycine-release site. The inhibitor is likely to reach GlyT1 from the cytoplasmic leaflet of the plasma membrane. Our results define the mechanism of inhibition and enable the rational design of new, clinically efficacious GlyT1 inhibitors.
人甘氨酸转运蛋白 1（GlyT1）通过钠依赖氯离子依赖性重摄取甘氨酸来调节甘氨酸介导的神经元兴奋和抑制。抑制 GlyT1 可延长神经递质信号传递，长期以来一直是开发治疗广泛中枢神经系统疾病（包括精神分裂症和认知障碍）的关键策略。在这里，我们使用合成单域抗体（sybody）和连续同步辐射晶体学，以 3.4Å 的分辨率确定了 GlyT1 与苯甲酰哌嗪化学型抑制剂复合物的结构。我们发现，抑制剂将 GlyT1 锁定在内向开放构象，并结合在释放途径的细胞内门，与甘氨酸释放位点重叠。抑制剂可能从质膜的细胞质小叶到达 GlyT1。我们的研究结果定义了抑制机制，并能够合理设计新的、临床有效的 GlyT1 抑制剂。
