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- PDB-9j8c: Human Glycine Transporter 1 in the Sarcosine-Bound State with an ... -

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Basic information

Entry
Database: PDB / ID: 9j8c
TitleHuman Glycine Transporter 1 in the Sarcosine-Bound State with an Occluded Conformation
ComponentsIsoform GlyT-1B of Sodium- and chloride-dependent glycine transporter 1
KeywordsMEMBRANE PROTEIN / human glycine transporter 1 / GlyT1 / sarcosine
Function / homology
Function and homology information


glycine:sodium symporter activity / regulation of synaptic transmission, glycinergic / glycine transmembrane transporter activity / positive regulation of heme biosynthetic process / glycine import across plasma membrane / glycine transport / positive regulation of hemoglobin biosynthetic process / dense core granule / amino acid:sodium symporter activity / Na+/Cl- dependent neurotransmitter transporters ...glycine:sodium symporter activity / regulation of synaptic transmission, glycinergic / glycine transmembrane transporter activity / positive regulation of heme biosynthetic process / glycine import across plasma membrane / glycine transport / positive regulation of hemoglobin biosynthetic process / dense core granule / amino acid:sodium symporter activity / Na+/Cl- dependent neurotransmitter transporters / neurotransmitter transport / parallel fiber to Purkinje cell synapse / lateral plasma membrane / transport across blood-brain barrier / sodium ion transmembrane transport / hippocampal mossy fiber to CA3 synapse / basal plasma membrane / synaptic vesicle membrane / presynaptic membrane / basolateral plasma membrane / postsynaptic 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
CHOLESTEROL / SARCOSINE / Sodium- and chloride-dependent glycine transporter 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsWei, Y. / Li, N. / Li, R. / Zhao, Y.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)92157102 China
CitationJournal: Nat Commun / Year: 2025
Title: Modulation of the human GlyT1 by clinical drugs and cholesterol.
Authors: Na Li / Yiqing Wei / Renjie Li / Yufei Meng / Jun Zhao / Qinru Bai / Gang Wang / Yan Zhao /
Abstract: Glycine transporter 1 (GlyT1) is a key player in shaping extracellular glutamatergic signaling processes and holds promise for treating cognitive impairments associated with schizophrenia by ...Glycine transporter 1 (GlyT1) is a key player in shaping extracellular glutamatergic signaling processes and holds promise for treating cognitive impairments associated with schizophrenia by inhibiting its activity and thus enhancing the function of NMDA receptors. Despite its significant role in physiological and pharmacology, its modulation mechanism by clinical drugs and internal lipids remains elusive. Here, we determine cryo-EM structures of GlyT1 in its apo state and in complex with clinical trial drugs iclepertin and sarcosine. The GlyT1 in its apo state is determined in three distinct conformations, exhibiting a conformational equilibrium of the transport cycle. The complex structures with inhibitor iclepertin and sarcosine elucidate their unique binding poses with GlyT1. Three binding sites of cholesterol are determined in GlyT1, two of which are conformation-dependent. Transport kinetics studies reveal that a delicate binding equilibrium for cholesterol is crucial for the conformational transition of GlyT1. This study significantly enhances our understanding of the physiological and pharmacological aspects of GlyT1.
History
DepositionAug 21, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Mar 5, 2025Provider: repository / Type: Initial release
Revision 1.0Mar 5, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Mar 5, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
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Revision 1.0Mar 5, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Mar 5, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Mar 19, 2025Group: Data collection / Database references / Category: citation / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Isoform GlyT-1B of Sodium- and chloride-dependent glycine transporter 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,8648
Polymers72,5331
Non-polymers1,3307
Water25214
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Isoform GlyT-1B of Sodium- and chloride-dependent glycine transporter 1 / GlyT-1 / GlyT1 / Solute carrier family 6 member 9


Mass: 72533.148 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC6A9 / Cell line (production host): HEK293F / Production host: Homo sapiens (human) / References: UniProt: P48067

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Non-polymers , 5 types, 21 molecules

#2: Chemical ChemComp-SAR / SARCOSINE


Type: peptide linking / Mass: 89.093 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H7NO2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C27H46O / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 14 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: human glycine transporter 1 (GlyT1) / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE / Humidity: 100 %

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 639501 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0024550
ELECTRON MICROSCOPYf_angle_d0.5026221
ELECTRON MICROSCOPYf_dihedral_angle_d6.341619
ELECTRON MICROSCOPYf_chiral_restr0.039693
ELECTRON MICROSCOPYf_plane_restr0.004750

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