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- PDB-8wfj: human glycine transporter 1 in complex with ALX-5407 in inward fa... -

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Basic information

Entry
Database: PDB / ID: 8wfj
Titlehuman glycine transporter 1 in complex with ALX-5407 in inward facing conformation
ComponentsSodium- and chloride-dependent glycine transporter 1
KeywordsMEMBRANE PROTEIN / GlyT1 / ALX-5407 / inward-open
Function / homology
Function and homology information


glycine:sodium symporter activity / regulation of synaptic transmission, glycinergic / glycine transmembrane transporter activity / negative regulation of NMDA glutamate receptor activity / positive regulation of heme biosynthetic process / glycine import across plasma membrane / glycine transport / synaptic transmission, glycinergic / positive regulation of hemoglobin biosynthetic process / dense core granule ...glycine:sodium symporter activity / regulation of synaptic transmission, glycinergic / glycine transmembrane transporter activity / negative regulation of NMDA glutamate receptor activity / positive regulation of heme biosynthetic process / glycine import across plasma membrane / glycine transport / synaptic transmission, glycinergic / positive regulation of hemoglobin biosynthetic process / dense core granule / Na+/Cl- dependent neurotransmitter transporters / parallel fiber to Purkinje cell synapse / neurotransmitter transport / transport across blood-brain barrier / lateral plasma membrane / 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
: / Sodium- and chloride-dependent glycine transporter 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.35 Å
AuthorsWei, Y. / Zhao, Y.
Funding support China, 1items
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, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 3, 2024Provider: repository / Type: Initial release
Revision 1.1Apr 17, 2024Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.page_first

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Sodium- and chloride-dependent glycine transporter 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,9272
Polymers72,5331
Non-polymers3931
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 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
#2: Chemical ChemComp-W5F / ALX5407 / 2-[[(3~{R})-3-(4-fluorophenyl)-3-(4-phenylphenoxy)propyl]-methyl-amino]ethanoic acid / ALX-5407 / (R)-NFPS


Mass: 393.451 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H24FNO3 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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 / 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

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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: 3.35 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 154181 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0044354
ELECTRON MICROSCOPYf_angle_d0.6615938
ELECTRON MICROSCOPYf_dihedral_angle_d5.032580
ELECTRON MICROSCOPYf_chiral_restr0.041653
ELECTRON MICROSCOPYf_plane_restr0.008728

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