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- PDB-9w8q: Transport and inhibition mechanisms of human glycine transporter 2 -

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Basic information

Entry
Database: PDB / ID: 9w8q
TitleTransport and inhibition mechanisms of human glycine transporter 2
ComponentsSodium- and chloride-dependent glycine transporter 2
KeywordsTRANSPORT PROTEIN / GlyT2 / membrane transport protein / Opiranserin
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsWu, J.X. / Ji, W.M. / Yu, Y.Z.
Funding support China, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32371266 China
National Natural Science Foundation of China (NSFC)ZYGXQNJSKYCXNLZCXM-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, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jun 24, 2026Provider: repository / Type: Initial release
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Structure visualization

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Assembly

Deposited unit
A: Sodium- and chloride-dependent glycine transporter 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,2712
Polymers66,8581
Non-polymers4131
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Sodium- and chloride-dependent glycine transporter 2 / GlyT-2 / GlyT2 / Solute carrier family 6 member 5


Mass: 66858.484 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC6A5, GLYT2, NET1 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q9Y345
#2: Chemical ChemComp-A1EF1 / ~{N}-[[1-(dimethylamino)cyclopentyl]methyl]-3,5-dimethoxy-4-phenylmethoxy-benzamide


Mass: 412.522 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H32N2O4 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: hGlyT2 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
2PHENIXmodel refinement
13cryoSPARC3D reconstruction
CTF correctionType: NONE
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 199203 / Symmetry type: POINT
RefinementHighest resolution: 3.2 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0034559
ELECTRON MICROSCOPYf_angle_d0.5566217
ELECTRON MICROSCOPYf_dihedral_angle_d3.906594
ELECTRON MICROSCOPYf_chiral_restr0.04692
ELECTRON MICROSCOPYf_plane_restr0.005756

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