2. Academic Validation
  3. Modulation of the human GlyT1 by clinical drugs and cholesterol

Modulation of the human GlyT1 by clinical drugs and cholesterol

  • Nat Commun. 2025 Mar 11;16(1):2412. doi: 10.1038/s41467-025-57613-z.
Na Li # 1,  Yiqing Wei # 2 3,  Renjie Li # 2 3,  Yufei Meng # 2 3,  Jun Zhao 4,  Qinru Bai 2 3,  Gang Wang 5,  Yan Zhao 6 7
Affiliations

Affiliations

  • 1 Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
  • 2 Key Laboratory of Biomacromolecules (CAS), National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
  • 3 College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.
  • 4 Peking University Institute of Advanced Agricultural Sciences, Shandong Laboratory of Advanced Agricultural Sciences at Weifang, Weifang, Shandong, China.
  • 5 Beijing Key Laboratory of Mental Disorders, National Clinical Research Center for Mental Disorders & National Center for Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China. gangwangdoc@ccmu.edu.cn.
  • 6 Key Laboratory of Biomacromolecules (CAS), National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. zhaoy@ibp.ac.cn.
  • 7 Beijing Key Laboratory of Mental Disorders, National Clinical Research Center for Mental Disorders & National Center for Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China. zhaoy@ibp.ac.cn.
  • # Contributed equally.
PMID: 40069141 DOI: 10.1038/s41467-025-57613-z
Abstract

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.

Figures
Products