8wfl

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

spinqualitylabelsall models 8wfl, resolution 3.03Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D 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: W5X 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] Sodium- and chloride-dependent glycine transporter. Sodium- and chloride-dependent glycine transporter. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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