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Yorodumi- PDB-8wfj: human glycine transporter 1 in complex with ALX-5407 in inward fa... -
+Open data
-Basic information
Entry | Database: PDB / ID: 8wfj | ||||||
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Title | human glycine transporter 1 in complex with ALX-5407 in inward facing conformation | ||||||
Components | Sodium- and chloride-dependent glycine transporter 1 | ||||||
Keywords | MEMBRANE PROTEIN / GlyT1 / ALX-5407 / inward-open | ||||||
Function / homology | Function and homology information glycine:sodium symporter activity / regulation of synaptic transmission, glycinergic / glycine transmembrane transporter activity / glycine import across plasma membrane / negative regulation of NMDA glutamate receptor activity / positive regulation of heme biosynthetic process / glycine transport / positive regulation of hemoglobin biosynthetic process / dense core granule / Na+/Cl- dependent neurotransmitter transporters ...glycine:sodium symporter activity / regulation of synaptic transmission, glycinergic / glycine transmembrane transporter activity / glycine import across plasma membrane / negative regulation of NMDA glutamate receptor activity / positive regulation of heme biosynthetic process / glycine transport / positive regulation of hemoglobin biosynthetic process / dense core granule / Na+/Cl- dependent neurotransmitter transporters / synaptic transmission, glycinergic / neurotransmitter transport / parallel fiber to Purkinje cell synapse / transport across blood-brain barrier / sodium ion transmembrane transport / lateral plasma membrane / hippocampal mossy fiber to CA3 synapse / basal plasma membrane / synaptic vesicle membrane / presynaptic membrane / postsynaptic membrane / basolateral plasma membrane / postsynaptic density / endosome / apical plasma membrane / membrane / plasma membrane Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.35 Å | ||||||
Authors | Wei, Y. / Zhao, Y. | ||||||
Funding support | China, 1items
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Citation | Journal: Cell / Year: 2024 Title: Transport mechanism and pharmacology of the human GlyT1. Authors: Yiqing Wei / Renjie Li / Yufei Meng / Tuo Hu / Jun Zhao / Yiwei Gao / Qinru Bai / Na Li / Yan Zhao / Abstract: 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 ...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. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8wfj.cif.gz | 115.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8wfj.ent.gz | 86.6 KB | Display | PDB format |
PDBx/mmJSON format | 8wfj.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/wf/8wfj ftp://data.pdbj.org/pub/pdb/validation_reports/wf/8wfj | HTTPS FTP |
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-Related structure data
Related structure data | 37493MC 8wfiC 8wfkC 8wflC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | Mass: 72533.148 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: SLC6A9 / Cell line (production host): HEK293F / Production host: Homo sapiens (human) / References: UniProt: P48067 |
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#2: Chemical | ChemComp-W5F / Mass: 393.451 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H24FNO3 / Feature type: SUBJECT OF INVESTIGATION |
Has ligand of interest | Y |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: human glycine transporter 1 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT |
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Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Homo sapiens (human) |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2200 nm / Nominal defocus min: 1200 nm |
Image recording | Electron dose: 60 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
-Processing
CTF correction | Type: PHASE FLIPPING ONLY | ||||||||||||||||||||||||
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3D reconstruction | Resolution: 3.35 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 154181 / Symmetry type: POINT | ||||||||||||||||||||||||
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