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- EMDB-37492: human glycine transporter 1 in complex with glycine in occluded c... -

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Basic information

Entry
Database: EMDB / ID: EMD-37492
Titlehuman glycine transporter 1 in complex with glycine in occluded conformation
Map data
Sample
  • Complex: human glycine transporter 1 (GlyT1)
    • Protein or peptide: Isoform GlyT-1B of Sodium- and chloride-dependent glycine transporter 1
  • Ligand: GLYCINE
  • Ligand: CHLORIDE ION
  • Ligand: SODIUM ION
  • Ligand: water
KeywordsGlyT1 / glycine / MEMBRANE PROTEIN
Function / homology
Function and homology information


regulation of synaptic transmission, glycinergic / glycine secretion, neurotransmission / glycine transmembrane transporter activity / glycine:sodium symporter activity / positive regulation of heme biosynthetic process / neurotransmitter uptake / glycine import across plasma membrane / glycine transport / positive regulation of hemoglobin biosynthetic process / amino acid:sodium symporter activity ...regulation of synaptic transmission, glycinergic / glycine secretion, neurotransmission / glycine transmembrane transporter activity / glycine:sodium symporter activity / positive regulation of heme biosynthetic process / neurotransmitter uptake / glycine import across plasma membrane / glycine transport / positive regulation of hemoglobin biosynthetic process / amino acid:sodium symporter activity / dense core granule / SLC-mediated transport of neurotransmitters / parallel fiber to Purkinje cell synapse / lateral plasma membrane / transport across blood-brain barrier / sodium ion transmembrane transport / basal plasma membrane / hippocampal mossy fiber to CA3 synapse / synaptic vesicle membrane / presynaptic membrane / basolateral plasma membrane / postsynaptic membrane / endosome / postsynaptic density / apical plasma membrane / membrane / plasma membrane
Similarity search - Function
Sodium:neurotransmitter symporter, glycine, type 1 / Sodium:neurotransmitter symporter family signature 2. / Sodium:neurotransmitter symporter family signature 1. / Sodium:neurotransmitter symporter / Sodium:neurotransmitter symporter superfamily / Sodium:neurotransmitter symporter family / Sodium:neurotransmitter symporter family profile.
Similarity search - Domain/homology
Sodium- and chloride-dependent glycine transporter 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.58 Å
AuthorsWei Y / Zhao Y
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)92157102 China
CitationJournal: 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
DepositionSep 19, 2023-
Header (metadata) releaseApr 3, 2024-
Map releaseApr 3, 2024-
UpdateJul 2, 2025-
Current statusJul 2, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_37492.png

Downloads & links

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Map

FileDownload / File: emd_37492.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 320 pix.
= 272. Å		0.85 Å/pix.
x 320 pix.
= 272. Å		0.85 Å/pix.
x 320 pix.
= 272. Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.85 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.9
Minimum - Maximum-3.1582139 - 4.1051273
Average (Standard dev.)-0.0009177096 (±0.06687107)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 272.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_37492_half_map_1.map
Projections & Slices
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Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_37492_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : human glycine transporter 1 (GlyT1)

EntireName: human glycine transporter 1 (GlyT1)
Components
  • Complex: human glycine transporter 1 (GlyT1)
    • Protein or peptide: Isoform GlyT-1B of Sodium- and chloride-dependent glycine transporter 1
  • Ligand: GLYCINE
  • Ligand: CHLORIDE ION
  • Ligand: SODIUM ION
  • Ligand: water

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Supramolecule #1: human glycine transporter 1 (GlyT1)

SupramoleculeName: human glycine transporter 1 (GlyT1) / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Isoform GlyT-1B of Sodium- and chloride-dependent glycine transpo...

MacromoleculeName: Isoform GlyT-1B of Sodium- and chloride-dependent glycine transporter 1
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 63.769484 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: RGNWGNQIEF VLTSVGYAVG LGNVWRFPYL CYRNAGGAFM FPYFIMLIFC GIPLFFMELS FGQFASQGCL GVWRISPMFK GVGYGMMVV STYIGIYYNV VICIAFYYFF SSMTHVLPWA YCNNPWNTHD CAGVLDASNL TNGSRPAALP SNLSHLLNHS L QRTSPSEE ...String:
RGNWGNQIEF VLTSVGYAVG LGNVWRFPYL CYRNAGGAFM FPYFIMLIFC GIPLFFMELS FGQFASQGCL GVWRISPMFK GVGYGMMVV STYIGIYYNV VICIAFYYFF SSMTHVLPWA YCNNPWNTHD CAGVLDASNL TNGSRPAALP SNLSHLLNHS L QRTSPSEE YWRLYVLKLS DDIGNFGEVR LPLLGCLGVS WLVVFLCLIR GVKSSGKVVY FTATFPYVVL TILFVRGVTL EG AFDGIMY YLTPQWDKIL AAKVWGDAAS QIFYSLGCAW GGLITMASYN KFHNNCYRDS VIISITNCAT SVYAGFVIFS ILG FMANHL GVDVSRVADH GPGLAFVAYP EALTLLPISP LWSLLFFFML ILLGLGTQFC LLETLVTAIV DEVGNEWILQ KKTY VTLGV AVAGFLLGIP LTSQAGIYWL LLMDNYAASF SLVVISCIMC VAIMYIYGHR NYFQDIQMML GFPPPLFFQI CWRFV SPAI IFFILVFTVI QYPITAYNHY QYPGWAVAIG FLMALSSVLC IPLYAMFRLC RTDGADLLQR LKNATKPSRD WGPALL EHR TGRYAP

UniProtKB: Sodium- and chloride-dependent glycine transporter 1

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Macromolecule #2: GLYCINE

MacromoleculeName: GLYCINE / type: ligand / ID: 2 / Number of copies: 1 / Formula: GLY
Molecular weightTheoretical: 75.067 Da
Chemical component information

ChemComp-GLY:
GLYCINE

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Macromolecule #3: CHLORIDE ION

MacromoleculeName: CHLORIDE ION / type: ligand / ID: 3 / Number of copies: 1 / Formula: CL
Molecular weightTheoretical: 35.453 Da

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Macromolecule #4: SODIUM ION

MacromoleculeName: SODIUM ION / type: ligand / ID: 4 / Number of copies: 2
Molecular weightTheoretical: 22.99 Da

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Macromolecule #5: water

MacromoleculeName: water / type: ligand / ID: 5 / Number of copies: 37 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300
VitrificationCryogen name: ETHANE / Chamber humidity: 100 %

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING ONLY
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.58 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 129157
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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