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- EMDB-37495: human glycine transporter 1 in complex with PF-03463275 in outwar... -

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Basic information

Entry
Database: EMDB / ID: EMD-37495
Titlehuman glycine transporter 1 in complex with PF-03463275 in outward facing conformation
Map data
Sample
  • Complex: human glycine transporter 1
    • Protein or peptide: Sodium- and chloride-dependent glycine transporter 1
  • Ligand: PF-3463275
KeywordsGlyT1 / PF03463275 / 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: 3.03 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_37495.png

Downloads & links

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Map

FileDownload / File: emd_37495.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 256 pix.
= 209.92 Å		0.82 Å/pix.
x 256 pix.
= 209.92 Å		0.82 Å/pix.
x 256 pix.
= 209.92 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.82 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.7
Minimum - Maximum-2.625826 - 5.863884
Average (Standard dev.)-0.0018239253 (±0.1451587)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 209.92 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_37495_half_map_1.map
Projections & Slices
AxesZYX

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Half map: #1

Fileemd_37495_half_map_2.map
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Sample components

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Entire : human glycine transporter 1

EntireName: human glycine transporter 1
Components
  • Complex: human glycine transporter 1
    • Protein or peptide: Sodium- and chloride-dependent glycine transporter 1
  • Ligand: PF-3463275

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Supramolecule #1: human glycine transporter 1

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

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Macromolecule #1: Sodium- and chloride-dependent glycine transporter 1

MacromoleculeName: 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: PF-3463275

MacromoleculeName: PF-3463275 / type: ligand / ID: 2 / Number of copies: 1 / Formula: W5X
Molecular weightTheoretical: 376.856 Da

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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

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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: OTHER
Final angle assignmentType: ANGULAR RECONSTITUTION
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.03 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 53950

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