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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 IONChloride
  • Ligand: SODIUM IONSodium
  • Ligand: water
KeywordsGlyT1 / glycine / MEMBRANE PROTEIN
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
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-
UpdateApr 17, 2024-
Current statusApr 17, 2024Processing 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)
Voxel sizeX=Y=Z: 0.85 Å
Density
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
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_37492_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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: GLYCINE
  • Ligand: CHLORIDE IONChloride
  • Ligand: SODIUM IONSodium
  • 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 / 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 / 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
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.2 µm
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 60.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

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

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