Key Laboratory of Biomacromolecules (CAS), National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
Peking University Institute of Advanced Agricultural Sciences, Shandong Laboratory of Advanced Agricultural Sciences at Weifang, Weifang, Shandong 261000, China.
Cell. 2024 Mar 28;187(7):1719-1732.e14. doi: 10.1016/j.cell.2024.02.026. Epub 2024 Mar 20.
The glycine transporter 1 (GlyT1) plays a crucial role in the regulation of both inhibitory and excitatory neurotransmission by removing glycine from the synaptic cleft. Given its close association with glutamate/glycine co-activated NMDA receptors (NMDARs), GlyT1 has emerged as a central target for the treatment of schizophrenia, which is often linked to hypofunctional NMDARs. Here, we report the cryo-EM structures of GlyT1 bound with substrate glycine and drugs ALX-5407, SSR504734, and PF-03463275. These structures, captured at three fundamental states of the transport cycle-outward-facing, occluded, and inward-facing-enable us to illustrate a comprehensive blueprint of the conformational change associated with glycine reuptake. Additionally, we identified three specific pockets accommodating drugs, providing clear insights into the structural basis of their inhibitory mechanism and selectivity. Collectively, these structures offer significant insights into the transport mechanism and recognition of substrate and anti-schizophrenia drugs, thus providing a platform to design small molecules to treat schizophrenia.
甘氨酸转运体 1（GlyT1）在调节抑制性和兴奋性神经递质传递中起着至关重要的作用，它能将甘氨酸从突触间隙中清除。鉴于其与谷氨酸/甘氨酸共激活的 NMDA 受体（NMDARs）密切相关，GlyT1 已成为治疗精神分裂症的重要靶点，而精神分裂症通常与 NMDAR 功能低下有关。在这里，我们报告了与底物甘氨酸以及药物 ALX-5407、SSR504734 和 PF-03463275 结合的 GlyT1 的冷冻电镜结构。这些结构分别处于转运循环的三个基本状态——向外开放、内陷关闭和向内开放，使我们能够阐明与甘氨酸再摄取相关的构象变化的综合蓝图。此外，我们还确定了三个容纳药物的特定口袋，为它们的抑制机制和选择性的结构基础提供了清晰的认识。总之，这些结构为转运机制以及底物和抗精神分裂症药物的识别提供了重要的见解，为设计小分子药物治疗精神分裂症提供了一个平台。
