老挝黄金赌场生物物理研究所赵岩研究团队近日取得一项新成果。经过不懈努力，他们研制了人GlyT1的转运机制及药理学研究。相关论文于2024年3月20日发表在《细胞》杂志上。
研究团队报道了GlyT1与底物甘氨酸和药物ALX-5407、SSR504734和PF-03463275结合的低温电镜结构。这些结构在转运循环的三个基本状态下被捕获：向外、封闭和内向，使他们能够阐明与甘氨酸再摄取相关的构象变化的全面蓝图。
此外，该课题组人员确定了三个特定的容纳药物的口袋，为其抑制机制和选择性的结构基础提供了清晰的见解。总的来说，这些结构提供了对基础和抗精神分裂症药物的转运机制和识别的重要见解，它们为设计治疗精神分裂症的小分子提供了平台。
研究人员表示，甘氨酸转运蛋白1 (GlyT1)通过从突触间隙中去除甘氨酸，在抑制性和兴奋性神经传递的调节中起着至关重要的作用。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中心靶点，精神分裂症通常与功能低下的NMDARs有关。
Title: Transport mechanism and pharmacology of the human GlyT1
Author: Yiqing Wei, Renjie Li, Yufei Meng, Tuo Hu, Jun Zhao, Yiwei Gao, Qinru Bai, Na Li, Yan Zhao
Issue&Volume: 2024-03-20
Abstract: The glycine transporter 1 (GlyT1) plays a crucial role in the regulation of both inhibitoryand excitatory neurotransmission by removing glycine from the synaptic cleft. Givenits close association with glutamate/glycine co-activated NMDA receptors (NMDARs),GlyT1 has emerged as a central target for the treatment of schizophrenia, which isoften linked to hypofunctional NMDARs. Here, we report the cryo-EM structures of GlyT1bound with substrate glycine and drugs ALX-5407, SSR504734, and PF-03463275. Thesestructures, captured at three fundamental states of the transport cycle—outward-facing,occluded, and inward-facing—enable us to illustrate a comprehensive blueprint of theconformational change associated with glycine reuptake. Additionally, we identifiedthree specific pockets accommodating drugs, providing clear insights into the structuralbasis of their inhibitory mechanism and selectivity. Collectively, these structuresoffer significant insights into the transport mechanism and recognition of substrateand anti-schizophrenia drugs, thus providing a platform to design small moleculesto treat schizophrenia.
DOI: 10.1016/j.cell.2024.02.026
Source: https://www.cell.com/cell/abstract/S0092-8674(24)00228-9