8wfj

human glycine transporter 1 in complex with ALX-5407 in inward facing conformation

spinqualitylabelsall models 8wfj, resolution 3.35Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8wfj 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 3.35Å Ligands: W5F Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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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