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- EMDB-65747: Transport and inhibition mechanisms of human glycine transporter 2 -

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Basic information

Entry
Database: EMDB / ID: EMD-65747
TitleTransport and inhibition mechanisms of human glycine transporter 2
Map data
Sample
  • Complex: hGlyT2
    • Protein or peptide: Sodium- and chloride-dependent glycine transporter 2
  • Ligand: 4-butoxy-~{N}-[[4-(dimethylamino)oxan-4-yl]methyl]-3,5-dimethoxy-benzamide
  • Ligand: SODIUM ION
  • Ligand: CHLORIDE ION
KeywordsGlyT2 / membrane transport protein / Opiranserin / TRANSPORT PROTEIN
Function / homology
Function and homology information


Defective SLC6A5 causes hyperekplexia 3 (HKPX3) / glycine:sodium symporter activity / synaptic transmission, glycinergic / glycine import across plasma membrane / dense core granule / SLC-mediated transport of neurotransmitters / neurotransmitter transport / sodium ion transmembrane transport / chemical synaptic transmission / endosome ...Defective SLC6A5 causes hyperekplexia 3 (HKPX3) / glycine:sodium symporter activity / synaptic transmission, glycinergic / glycine import across plasma membrane / dense core granule / SLC-mediated transport of neurotransmitters / neurotransmitter transport / sodium ion transmembrane transport / chemical synaptic transmission / endosome / synapse / membrane / metal ion binding / plasma membrane
Similarity search - Function
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 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.73 Å
AuthorsWu JX / Yu YZ / Ji WM
Funding support China, 2 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32371266 China
National Natural Science Foundation of China (NSFC)ZYGXONJSKYCXNLZCXM-B2 China
CitationJournal: Nat Commun / Year: 2026
Title: Transport and inhibition mechanisms of human glycine transporter 2.
Authors: Wenming Ji / Yuanzhi Yu / Zirui Liu / Junwen Su / Qianyu Wang / Mulin Lai / Jing-Xiang Wu /
Abstract: Neuronal human glycine transporter 2 (hGlyT2) plays a critical role in maintaining glycinergic neurotransmission via the reuptake of glycine into presynaptic neurons by using the driving force of ...Neuronal human glycine transporter 2 (hGlyT2) plays a critical role in maintaining glycinergic neurotransmission via the reuptake of glycine into presynaptic neurons by using the driving force of sodium and chloride ion gradients. hGlyT2 represents an important drug target for analgesic purpose. However, its structure and the molecular mechanisms remain elusive. Here, we report structures of hGlyT2 in three functional states, including the apo state, the substrate glycine-bound state, and the inhibitor-bound states. The apo state of hGlyT2 adopts an inward conformation. The substrate glycine binds at the central pocket of hGlyT2 in its occluded conformation. Both inhibitors, ORG25543 and opiranserin, bind to an allosteric site, which is vertical to the extracellular tunnel, buried under the extracellular loop 4 (EL4) and near to the transmembrane helix 1b (TM1b). These inhibitors act as wedges to prevent the inward movement of TM1b and closure of the extracellular gate. Further structural analysis reveals both global and local conformational changes associated with the ions and glycine binding and release. These structures define the mechanisms governing transport and allosteric inhibition in hGlyT2, providing a blueprint for further development of non-opioid analgesics targeting hGlyT2.
History
DepositionAug 7, 2025-
Header (metadata) releaseJun 24, 2026-
Map releaseJun 24, 2026-
UpdateJun 24, 2026-
Current statusJun 24, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_65747.png

Downloads & links

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Map

FileDownload / File: emd_65747.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.)
1.07 Å/pix.
x 256 pix.
= 273.152 Å		1.07 Å/pix.
x 256 pix.
= 273.152 Å		1.07 Å/pix.
x 256 pix.
= 273.152 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.067 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.6
Minimum - Maximum-5.4590282 - 8.334603
Average (Standard dev.)-0.0035737115 (±0.15457812)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 273.152 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_65747_msk_1.map
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Half map: #2

Fileemd_65747_half_map_1.map
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Half map: #1

Fileemd_65747_half_map_2.map
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Sample components

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Entire : hGlyT2

EntireName: hGlyT2
Components
  • Complex: hGlyT2
    • Protein or peptide: Sodium- and chloride-dependent glycine transporter 2
  • Ligand: 4-butoxy-~{N}-[[4-(dimethylamino)oxan-4-yl]methyl]-3,5-dimethoxy-benzamide
  • Ligand: SODIUM ION
  • Ligand: CHLORIDE ION

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Supramolecule #1: hGlyT2

SupramoleculeName: hGlyT2 / 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 2

MacromoleculeName: Sodium- and chloride-dependent glycine transporter 2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 67.057695 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QGDENKARGN WSSKLDFILS MVGYAVGLGN VWRFPYLAFQ NGGGAFLIPY LMMLALAGLP IFFLEVSLGQ FASQGPVSVW KAIPALQGC GIAMLIISVL IAIYYNVIIC YTLFYLFASF VSVLPWGSCN NPWNTPECKD KTKLLLDSCV ISDHPKIQIK N STFCMTAY ...String:
QGDENKARGN WSSKLDFILS MVGYAVGLGN VWRFPYLAFQ NGGGAFLIPY LMMLALAGLP IFFLEVSLGQ FASQGPVSVW KAIPALQGC GIAMLIISVL IAIYYNVIIC YTLFYLFASF VSVLPWGSCN NPWNTPECKD KTKLLLDSCV ISDHPKIQIK N STFCMTAY PNVTMVNFTS QANKTFVSGS EEYFKYFVLK ISAGIEYPGE IRWPLALCLF LAWVIVYASL AKGIKTSGKV VY FTATFPY VVLVILLIRG VTLPGAGAGI WYFITPKWEK LTDATVWKDA ATQIFFSLSA AWGGLITLSS YNKFHNNCYR DTL IVTCTN SATSIFAGFV IFSVIGFMAN ERKVNIENVA DQGPGIAFVV YPEALTRLPL SPFWAIIFFL MLLTLGLDTM FATI ETIVT SISDEFPKYL RTHKPVFTLG CCICFFIMGF PMITQGGIYM FQLVDTYAAS YALVIIAIFE LVGISYVYGL QRFCE DIEM MIGFQPNIFW KVCWAFVTPT ILTFILCFSF YQWEPMTYGS YRYPNWSMVL GWLMLACSVI WIPIMFVIKM HLAPGR FIE RLKLVCSPQP DWGPFLAQHR GERYKNMIDP LA

UniProtKB: Sodium- and chloride-dependent glycine transporter 2

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Macromolecule #2: 4-butoxy-~{N}-[[4-(dimethylamino)oxan-4-yl]methyl]-3,5-dimethoxy-...

MacromoleculeName: 4-butoxy-~{N}-[[4-(dimethylamino)oxan-4-yl]methyl]-3,5-dimethoxy-benzamide
type: ligand / ID: 2 / Number of copies: 1 / Formula: A1EF3
Molecular weightTheoretical: 394.505 Da

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Macromolecule #3: SODIUM ION

MacromoleculeName: SODIUM ION / type: ligand / ID: 3 / Number of copies: 1
Molecular weightTheoretical: 22.99 Da

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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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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.73 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 272052
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
FSC plot (resolution estimation)

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