8wfl

From Proteopedia

human glycine transporter 1 in complex with PF-03463275 in outward facing conformation

Structural highlights

8wfl is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.03Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

SC6A9_HUMAN Atypical glycine encephalopathy;Infantile glycine encephalopathy. The disease is caused by variants affecting the gene represented in this entry.

Function

SC6A9_HUMAN Sodium- and chloride-dependent glycine transporter (PubMed:8183239). Essential for regulating glycine concentrations at inhibitory glycinergic synapses.[UniProtKB:P28571]^[1] Sodium- and chloride-dependent glycine transporter.^[2] Sodium- and chloride-dependent glycine transporter.^[3]

Publication Abstract from PubMed

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.

Transport mechanism and pharmacology of the human GlyT1.,Wei Y, Li R, Meng Y, Hu T, Zhao J, Gao Y, Bai Q, Li N, Zhao Y Cell. 2024 Mar 28;187(7):1719-1732.e14. doi: 10.1016/j.cell.2024.02.026. Epub , 2024 Mar 20. PMID:38513663^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Kim KM, Kingsmore SF, Han H, Yang-Feng TL, Godinot N, Seldin MF, Caron MG, Giros B. Cloning of the human glycine transporter type 1: molecular and pharmacological characterization of novel isoform variants and chromosomal localization of the gene in the human and mouse genomes. Mol Pharmacol. 1994 Apr;45(4):608-17 PMID:8183239
↑ Kim KM, Kingsmore SF, Han H, Yang-Feng TL, Godinot N, Seldin MF, Caron MG, Giros B. Cloning of the human glycine transporter type 1: molecular and pharmacological characterization of novel isoform variants and chromosomal localization of the gene in the human and mouse genomes. Mol Pharmacol. 1994 Apr;45(4):608-17 PMID:8183239
↑ Kim KM, Kingsmore SF, Han H, Yang-Feng TL, Godinot N, Seldin MF, Caron MG, Giros B. Cloning of the human glycine transporter type 1: molecular and pharmacological characterization of novel isoform variants and chromosomal localization of the gene in the human and mouse genomes. Mol Pharmacol. 1994 Apr;45(4):608-17 PMID:8183239
↑ Wei Y, Li R, Meng Y, Hu T, Zhao J, Gao Y, Bai Q, Li N, Zhao Y. Transport mechanism and pharmacology of the human GlyT1. Cell. 2024 Mar 28;187(7):1719-1732.e14. PMID:38513663 doi:10.1016/j.cell.2024.02.026