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- EMDB-62424: Cryo-EM structure of glycine transporter 2 in complex with ORG25543 -

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Basic information

Entry
Database: EMDB / ID: EMD-62424
TitleCryo-EM structure of glycine transporter 2 in complex with ORG25543
Map data
Sample
  • Complex: Cryo-EM structure of glycine transporter 2 in complex with org25543
    • Protein or peptide: Transporter
  • Ligand: ~{N}-[[1-(dimethylamino)cyclopentyl]methyl]-3,5-dimethoxy-4-phenylmethoxy-benzamide
  • Ligand: CHOLESTEROL
KeywordsGLYT2 / PROTEIN STRUCTURE / MEMBRANE PROTEIN
Function / homology
Function and homology information


SLC-mediated transport of neurotransmitters / glycine:sodium symporter activity / synaptic transmission, glycinergic / glycine import across plasma membrane / sodium ion transmembrane transport / synapse / 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
Biological speciesXenopus tropicalis (tropical clawed frog)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsWang Y / Zhao Y
Funding support China, 1 items
OrganizationGrant numberCountry
Chinese Academy of Sciences China
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: Mechanisms of transport and analgesic compounds recognition by glycine transporter 2.
Authors: Yuhang Wang / Jiawei Su / Jun Zhao / Renjie Li / Qinru Bai / Hongyi Song / Yufei Meng / Qiao Ma / Yan Zhao /
Abstract: Glycine transporter 2 (GlyT2) regulates inhibitory glycinergic neurotransmission, and its inhibition potentiates glycinergic signaling, which is a promising strategy for managing neuropathic pain. ...Glycine transporter 2 (GlyT2) regulates inhibitory glycinergic neurotransmission, and its inhibition potentiates glycinergic signaling, which is a promising strategy for managing neuropathic pain. This study presents high-resolution structures of GlyT2 in its apo state and in complexes with the substrate glycine, analgesic inhibitors, captured in three functional states: outward-facing, occluded, and inward-facing. The glycine-bound structure reveals the binding mode of the substrate, Na and Cl. Specifically, we identified the Na3 binding site, offering fundamental insights into Na/Cl coupled substrate binding and conformational changes. Moreover, we clearly elucidate a previously unseen allosteric binding pocket for the lipid-based oleoyl-D-lysine, which acts as a wedge to stabilize GlyT2 in the outward-facing conformation and prevents its transition. Furthermore, the complex structures with small compounds ALX1393, opiranserin, and ORG25543 reveal their competitive and allosteric inhibition mechanisms. Overall, our study provides a solid foundation for understanding glycine reuptake mechanisms and developing effective and safer analgesic agents.
History
DepositionNov 15, 2024-
Header (metadata) releaseNov 19, 2025-
Map releaseNov 19, 2025-
UpdateDec 10, 2025-
Current statusDec 10, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_62424.png

Downloads & links

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Map

FileDownload / File: emd_62424.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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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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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.85 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.324
Minimum - Maximum-1.4948962 - 2.1068382
Average (Standard dev.)-0.0011769102 (±0.062451683)
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_62424_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_62424_half_map_2.map
Projections & Slices
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Histogram

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Sample components

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Entire : Cryo-EM structure of glycine transporter 2 in complex with org25543

EntireName: Cryo-EM structure of glycine transporter 2 in complex with org25543
Components
  • Complex: Cryo-EM structure of glycine transporter 2 in complex with org25543
    • Protein or peptide: Transporter
  • Ligand: ~{N}-[[1-(dimethylamino)cyclopentyl]methyl]-3,5-dimethoxy-4-phenylmethoxy-benzamide
  • Ligand: CHOLESTEROL

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Supramolecule #1: Cryo-EM structure of glycine transporter 2 in complex with org25543

SupramoleculeName: Cryo-EM structure of glycine transporter 2 in complex with org25543
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Xenopus tropicalis (tropical clawed frog)

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Macromolecule #1: Transporter

MacromoleculeName: Transporter / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Xenopus tropicalis (tropical clawed frog)
Molecular weightTheoretical: 66.663352 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GDENKARGNW SSKLDFILSM VGYAVGLGNV WRFPYLAFKN GGGAFLIPYL TMLALAGLPI FYMEVALGQF ASQGPISVWK AIPALQGCG IAMLIISVLI AIYYNVIICY TIFYLFASLV SVLPWASCTN PWNTPDCKDK DRLLLDSCII GSQPNIHIKN S TFCMTAYP ...String:
GDENKARGNW SSKLDFILSM VGYAVGLGNV WRFPYLAFKN GGGAFLIPYL TMLALAGLPI FYMEVALGQF ASQGPISVWK AIPALQGCG IAMLIISVLI AIYYNVIICY TIFYLFASLV SVLPWASCTN PWNTPDCKDK DRLLLDSCII GSQPNIHIKN S TFCMTAYP NLTLVNFTSH ANKSFVSGSE EYFKYNMLKI SAGIEYPGEI RWPLAICLFL AWTIVYASLA KGIKSSGKVV YF TATFPYV VLVILLIRGV TLPGAGDGIW WFIMPKWEKL MDAMVWKDAA TQIFFSLSAA WGGLITLSSY NKFHNNVYRD TLI VTCTNS ATSIFAGFVI FSVIGFMANE RKVNIENVAD QGPGIAFVVY PEALTRLPLS PFWAIIFFLM LLTLGLDTMF ATIE TIVTS VSDEFPKLLR PHKPLFTLIC CVAFFIMGFP MITQGGIYMF QLVDNYAASY SLVIIAIFEL VGISYVYGLQ RFCED IEMM IGFQPSRFWK VCWAFVTPTI LTFILCFSFY QWEPMTYGSY HYPTWSMVMG WLMLACSVIW IPVMFVIKMY LAPGTF IER LKLVCSPQPD WGPFLAKHRG ERYKNMID

UniProtKB: Transporter

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Macromolecule #2: ~{N}-[[1-(dimethylamino)cyclopentyl]methyl]-3,5-dimethoxy-4-pheny...

MacromoleculeName: ~{N}-[[1-(dimethylamino)cyclopentyl]methyl]-3,5-dimethoxy-4-phenylmethoxy-benzamide
type: ligand / ID: 2 / Number of copies: 1 / Formula: A1EF1
Molecular weightTheoretical: 412.522 Da

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Macromolecule #3: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 3 / Number of copies: 1 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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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 / Chamber humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k 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 / Cs: 2.7 mm / 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: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 101024
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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