Li Na, Wei Yiqing, Li Renjie, Meng Yufei, Zhao Jun, Bai Qinru, Wang Gang, Zhao Yan
Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
Key Laboratory of Biomacromolecules (CAS), National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Nat Commun. 2025 Mar 11;16(1):2412. doi: 10.1038/s41467-025-57613-z.
Glycine transporter 1 (GlyT1) is a key player in shaping extracellular glutamatergic signaling processes and holds promise for treating cognitive impairments associated with schizophrenia by inhibiting its activity and thus enhancing the function of NMDA receptors. Despite its significant role in physiological and pharmacology, its modulation mechanism by clinical drugs and internal lipids remains elusive. Here, we determine cryo-EM structures of GlyT1 in its apo state and in complex with clinical trial drugs iclepertin and sarcosine. The GlyT1 in its apo state is determined in three distinct conformations, exhibiting a conformational equilibrium of the transport cycle. The complex structures with inhibitor iclepertin and sarcosine elucidate their unique binding poses with GlyT1. Three binding sites of cholesterol are determined in GlyT1, two of which are conformation-dependent. Transport kinetics studies reveal that a delicate binding equilibrium for cholesterol is crucial for the conformational transition of GlyT1. This study significantly enhances our understanding of the physiological and pharmacological aspects of GlyT1.
甘氨酸转运体1（GlyT1）在塑造细胞外谷氨酸能信号传导过程中起着关键作用，通过抑制其活性从而增强NMDA受体功能，有望用于治疗与精神分裂症相关的认知障碍。尽管它在生理学和药理学中具有重要作用，但其受临床药物和内源性脂质的调节机制仍不清楚。在此，我们确定了处于无配体状态以及与临床试验药物艾考替哌和肌氨酸结合的GlyT1的冷冻电镜结构。处于无配体状态的GlyT1呈现出三种不同的构象，展示了转运循环的构象平衡。与抑制剂艾考替哌和肌氨酸的复合物结构阐明了它们与GlyT1独特的结合模式。在GlyT1中确定了三个胆固醇结合位点，其中两个是构象依赖性的。转运动力学研究表明，胆固醇的微妙结合平衡对于GlyT1的构象转变至关重要。这项研究显著增进了我们对GlyT1生理和药理学方面的理解。
