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- PDB-7y7y: Cryo-EM structure of human GABA transporter GAT1 bound with nipec... -

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Basic information

Entry
Database: PDB / ID: 7y7y
TitleCryo-EM structure of human GABA transporter GAT1 bound with nipecotic acid in NaCl solution in an inward-occluded state at 2.4 angstrom
ComponentsSodium- and chloride-dependent GABA transporter 1
KeywordsTRANSPORT PROTEIN / GABA transporter / GAT1 / Nipecotic acid / Tiagabine / Neurotransmitter / SLC6A1
Function / homology
Function and homology information


gamma-aminobutyric acid reuptake / Reuptake of GABA / inorganic anion import across plasma membrane / sodium:chloride symporter activity / gamma-aminobutyric acid transmembrane transporter activity / gamma-aminobutyric acid import / gamma-aminobutyric acid:sodium:chloride symporter activity / SLC-mediated transport of neurotransmitters / sodium ion import across plasma membrane / amino acid transport ...gamma-aminobutyric acid reuptake / Reuptake of GABA / inorganic anion import across plasma membrane / sodium:chloride symporter activity / gamma-aminobutyric acid transmembrane transporter activity / gamma-aminobutyric acid import / gamma-aminobutyric acid:sodium:chloride symporter activity / SLC-mediated transport of neurotransmitters / sodium ion import across plasma membrane / amino acid transport / associative learning / transport across blood-brain barrier / sodium ion transmembrane transport / chloride transmembrane transport / synapse organization / GABA-ergic synapse / memory / presynapse / chemical synaptic transmission / axon / neuronal cell body / cell surface / metal ion binding / membrane / plasma membrane
Similarity search - Function
Sodium:neurotransmitter symporter, GABA, GAT-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
(3R)-piperidine-3-carboxylic acid / Sodium- and chloride-dependent GABA transporter 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.4 Å
AuthorsZhu, A. / Huang, J. / Kong, F. / Tan, J. / Lei, J. / Yuan, Y. / Yan, C.
Funding support China, 1items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2020YFA0509301 China
CitationJournal: Nat Struct Mol Biol / Year: 2023
Title: Molecular basis for substrate recognition and transport of human GABA transporter GAT1.
Authors: Angqi Zhu / Junhao Huang / Fang Kong / Jiaxin Tan / Jianlin Lei / Yafei Yuan / Chuangye Yan /
Abstract: γ-Aminobutyric acid (GABA), an important inhibitory neurotransmitter in the central nervous system, is recycled through specific GABA transporters (GATs). GAT1, which is mainly expressed in the ...γ-Aminobutyric acid (GABA), an important inhibitory neurotransmitter in the central nervous system, is recycled through specific GABA transporters (GATs). GAT1, which is mainly expressed in the presynaptic terminals of axons, is a potential drug target of neurological disorders due to its essential role in GABA transport. Here we report four cryogenic electron microscopy structures of human GAT1, at resolutions of 2.2-3.2 Å. GAT1 in substrate-free form or in complex with the antiepileptic drug tiagabine exhibits an inward-open conformation. In the presence of GABA or nipecotic acid, inward-occluded structures are captured. The GABA-bound structure reveals an interaction network bridged by hydrogen bonds and ion coordination for GABA recognition. The substrate-free structure unwinds the last helical turn of transmembrane helix TM1a to release sodium ions and substrate. Complemented by structure-guided biochemical analyses, our studies reveal detailed mechanism of GABA recognition and transport, and elucidate mode of action of the inhibitors, nipecotic acid and tiagabine.
History
DepositionJun 22, 2022Deposition site: PDBJ / Processing site: PDBJ
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Revision 1.2Oct 9, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)71,7708
Polymers70,8961
Non-polymers8747
Water97354
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein / Sugars , 2 types, 4 molecules A

#1: Protein Sodium- and chloride-dependent GABA transporter 1 / GAT-1 / Solute carrier family 6 member 1


Mass: 70895.898 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC6A1, GABATR, GABT1, GAT1 / Production host: Homo sapiens (human) / References: UniProt: P30531
#3: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 4 types, 58 molecules

#2: Chemical ChemComp-ID7 / (3R)-piperidine-3-carboxylic acid / (R)-nipecotic acid


Mass: 129.157 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H11NO2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 54 / 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: GAT1 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.11 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenConc.: 8 mg/ml / Embedding 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: 1400 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18_3855: / Classification: refinement
EM software
IDNameCategory
8PHENIXmodel refinement
10cryoSPARCinitial Euler assignment
11cryoSPARCfinal Euler assignment
13cryoSPARC3D reconstruction
CTF correctionType: NONE
3D reconstructionResolution: 2.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1111920 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0054339
ELECTRON MICROSCOPYf_angle_d0.6755911
ELECTRON MICROSCOPYf_dihedral_angle_d8.982577
ELECTRON MICROSCOPYf_chiral_restr0.07651
ELECTRON MICROSCOPYf_plane_restr0.004719

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