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- EMDB-61227: Human Glycine Transporter 1 in the Sarcosine-Bound State with an ... -

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Basic information

Entry
Database: EMDB / ID: EMD-61227
TitleHuman Glycine Transporter 1 in the Sarcosine-Bound State with an 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: SARCOSINE
  • Ligand: CHOLESTEROL
  • Ligand: CHLORIDE ION
  • Ligand: SODIUM ION
  • Ligand: water
Keywordshuman glycine transporter 1 / GlyT1 / sarcosine / MEMBRANE PROTEIN
Function / homology
Function and homology information


glycine:sodium symporter activity / regulation of synaptic transmission, glycinergic / glycine transmembrane transporter activity / positive regulation of heme biosynthetic process / glycine import across plasma membrane / glycine transport / positive regulation of hemoglobin biosynthetic process / dense core granule / amino acid:sodium symporter activity / Na+/Cl- dependent neurotransmitter transporters ...glycine:sodium symporter activity / regulation of synaptic transmission, glycinergic / glycine transmembrane transporter activity / positive regulation of heme biosynthetic process / glycine import across plasma membrane / glycine transport / positive regulation of hemoglobin biosynthetic process / dense core granule / amino acid:sodium symporter activity / Na+/Cl- dependent neurotransmitter transporters / neurotransmitter transport / parallel fiber to Purkinje cell synapse / lateral plasma membrane / transport across blood-brain barrier / sodium ion transmembrane transport / hippocampal mossy fiber to CA3 synapse / basal plasma membrane / synaptic vesicle membrane / presynaptic membrane / basolateral plasma membrane / postsynaptic membrane / postsynaptic density / endosome / 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: 2.9 Å
AuthorsWei Y / Li N / Li R / Zhao Y
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)92157102 China
CitationJournal: Nat Commun / Year: 2025
Title: Modulation of the human GlyT1 by clinical drugs and cholesterol.
Authors: Na Li / Yiqing Wei / Renjie Li / Yufei Meng / Jun Zhao / Qinru Bai / Gang Wang / Yan Zhao /
Abstract: Glycine transporter 1 (GlyT1) is a key player in shaping extracellular glutamatergic signaling processes and holds promise for treating cognitive impairments associated with schizophrenia by ...Glycine transporter 1 (GlyT1) is a key player in shaping extracellular glutamatergic signaling processes and holds promise for treating cognitive impairments associated with schizophrenia by inhibiting its activity and thus enhancing the function of NMDA receptors. Despite its significant role in physiological and pharmacology, its modulation mechanism by clinical drugs and internal lipids remains elusive. Here, we determine cryo-EM structures of GlyT1 in its apo state and in complex with clinical trial drugs iclepertin and sarcosine. The GlyT1 in its apo state is determined in three distinct conformations, exhibiting a conformational equilibrium of the transport cycle. The complex structures with inhibitor iclepertin and sarcosine elucidate their unique binding poses with GlyT1. Three binding sites of cholesterol are determined in GlyT1, two of which are conformation-dependent. Transport kinetics studies reveal that a delicate binding equilibrium for cholesterol is crucial for the conformational transition of GlyT1. This study significantly enhances our understanding of the physiological and pharmacological aspects of GlyT1.
History
DepositionAug 21, 2024-
Header (metadata) releaseMar 5, 2025-
Map releaseMar 5, 2025-
UpdateMar 26, 2025-
Current statusMar 26, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_61227.png

Downloads & links

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Map

FileDownload / File: emd_61227.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 256 pix.
= 217.6 Å		0.85 Å/pix.
x 256 pix.
= 217.6 Å		0.85 Å/pix.
x 256 pix.
= 217.6 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.85 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.3
Minimum - Maximum-1.5054113 - 2.3935585
Average (Standard dev.)-0.00035227183 (±0.056960627)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 217.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_61227_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_61227_half_map_2.map
Projections & Slices
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Histogram

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: SARCOSINE
  • Ligand: CHOLESTEROL
  • 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: 72.533148 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSGGDTRAAI ARPRMAAAHG PVAPSSPEQN GAVPSEATKR DQNLKRGNWG NQIEFVLTSV GYAVGLGNVW RFPYLCYRNG GGAFMFPYF IMLIFCGIPL FFMELSFGQF ASQGCLGVWR ISPMFKGVGY GMMVVSTYIG IYYNVVICIA FYYFFSSMTH V LPWAYCNN ...String:
MSGGDTRAAI ARPRMAAAHG PVAPSSPEQN GAVPSEATKR DQNLKRGNWG NQIEFVLTSV GYAVGLGNVW RFPYLCYRNG GGAFMFPYF IMLIFCGIPL FFMELSFGQF ASQGCLGVWR ISPMFKGVGY GMMVVSTYIG IYYNVVICIA FYYFFSSMTH V LPWAYCNN PWNTHDCAGV LDASNLTNGS RPAALPSNLS HLLNHSLQRT SPSEEYWRLY VLKLSDDIGN FGEVRLPLLG CL GVSWLVV FLCLIRGVKS SGKVVYFTAT FPYVVLTILF VRGVTLEGAF DGIMYYLTPQ WDKILEAKVW GDAASQIFYS LGC AWGGLI TMASYNKFHN NCYRDSVIIS ITNCATSVYA GFVIFSILGF MANHLGVDVS RVADHGPGLA FVAYPEALTL LPIS PLWSL LFFFMLILLG LGTQFCLLET LVTAIVDEVG NEWILQKKTY VTLGVAVAGF LLGIPLTSQA GIYWLLLMDN YAASF SLVV ISCIMCVAIM YIYGHRNYFQ DIQMMLGFPP PLFFQICWRF VSPAIIFFIL VFTVIQYQPI TYNHYQYPGW AVAIGF LMA LSSVLCIPLY AMFRLCRTDG DTLLQRLKNA TKPSRDWGPA LLEHRTGRYA PTIAPSPEDG FEVQPLHPDK AQIPIVG SN GSSRLQDSRI

UniProtKB: Sodium- and chloride-dependent glycine transporter 1

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Macromolecule #2: SARCOSINE

MacromoleculeName: SARCOSINE / type: ligand / ID: 2 / Number of copies: 1 / Formula: SAR
Molecular weightTheoretical: 89.093 Da
Chemical component information

ChemComp-SAR:
SARCOSINE

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Macromolecule #3: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 3 / Number of copies: 3 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #4: CHLORIDE ION

MacromoleculeName: CHLORIDE ION / type: ligand / ID: 4 / Number of copies: 1 / Formula: CL
Molecular weightTheoretical: 35.453 Da

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Macromolecule #5: SODIUM ION

MacromoleculeName: SODIUM ION / type: ligand / ID: 5 / Number of copies: 2
Molecular weightTheoretical: 22.99 Da

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Macromolecule #6: water

MacromoleculeName: water / type: ligand / ID: 6 / Number of copies: 14 / 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
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

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 639501
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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