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- EMDB-60388: Human high-affinity choline transporter CHT1 bound to choline und... -

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Basic information

Entry
Database: EMDB / ID: EMD-60388
TitleHuman high-affinity choline transporter CHT1 bound to choline under NaCl condition, with sodium and chloride ions coordinated.
Map data
Sample
  • Complex: Human high-affinity choline transporter CHT1 bound to choline under NaCl condition, with sodium and chloride ions coordinated.
    • Protein or peptide: High affinity choline transporter 1
  • Ligand: CHOLINE ION
  • Ligand: SODIUM ION
  • Ligand: CHLORIDE ION
Keywordstransporter / STRUCTURAL PROTEIN
Function / homology
Function and homology information


choline:sodium symporter activity / Defective SLC5A7 causes distal hereditary motor neuronopathy 7A (HMN7A) / Defective SLC5A7 causes distal hereditary motor neuronopathy 7A (HMN7A) / acetylcholine biosynthetic process / Transport of bile salts and organic acids, metal ions and amine compounds / choline transmembrane transporter activity / Acetylcholine Neurotransmitter Release Cycle / choline transport / choline binding / neuromuscular synaptic transmission ...choline:sodium symporter activity / Defective SLC5A7 causes distal hereditary motor neuronopathy 7A (HMN7A) / Defective SLC5A7 causes distal hereditary motor neuronopathy 7A (HMN7A) / acetylcholine biosynthetic process / Transport of bile salts and organic acids, metal ions and amine compounds / choline transmembrane transporter activity / Acetylcholine Neurotransmitter Release Cycle / choline transport / choline binding / neuromuscular synaptic transmission / synaptic transmission, cholinergic / neurotransmitter transport / neuromuscular junction / transmembrane transport / synaptic vesicle membrane / presynaptic membrane / early endosome membrane / perikaryon / in utero embryonic development / axon / synapse / dendrite / membrane / plasma membrane
Similarity search - Function
: / Sodium/solute symporter / Sodium/glucose symporter superfamily / Sodium:solute symporter family / Sodium:solute symporter family profile.
Similarity search - Domain/homology
High affinity choline transporter 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.5 Å
AuthorsQiu Y / Gao Y / Zhao Y
Funding support China, 1 items
OrganizationGrant numberCountry
Chinese Academy of SciencesXDB37030304 China
CitationJournal: Structure / Year: 2025
Title: Ion coupling and inhibitory mechanisms of the human presynaptic high-affinity choline transporter CHT1.
Authors: Yunlong Qiu / Yiwei Gao / Qinru Bai / Yan Zhao /
Abstract: In cholinergic neurons, choline is the precursor of the excitatory neurotransmitter acetylcholine (ACh), which plays a fundamental role in the brain. The high-affinity choline transporter, CHT1, ...In cholinergic neurons, choline is the precursor of the excitatory neurotransmitter acetylcholine (ACh), which plays a fundamental role in the brain. The high-affinity choline transporter, CHT1, mediates the efficient recycling of choline to facilitate ACh synthesis in the presynapse. Here, we report high-resolution cryoelectron microscopic (cryo-EM) structures of CHT1 in complex with the inhibitors HC-3 and ML352, the substrate choline, and a substrate-free state. Our structures show distinct binding modes of the inhibitors with different chemical structures, revealing their inhibition mechanisms. Additionally, we observed a chloride ion that directly interacts with the substrate choline, thereby stabilizing its binding with CHT1. Two sodium ions, Na2 and Na3, were clearly identified, which we speculate might be involved in substrate binding and conformational transitions, respectively. Our structures provide molecular insights into the coupling mechanism of ion binding with substrate binding and conformational transitions, promoting our understanding of the ion-coupled substrate transport mechanism.
History
DepositionJun 3, 2024-
Header (metadata) releaseDec 4, 2024-
Map releaseDec 4, 2024-
UpdateFeb 26, 2025-
Current statusFeb 26, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_60388.png

Downloads & links

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Map

FileDownload / File: emd_60388.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 320 pix.
= 272. Å		0.85 Å/pix.
x 320 pix.
= 272. Å		0.85 Å/pix.
x 320 pix.
= 272. Å

Surface

Projections

Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.85 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.873
Minimum - Maximum-3.5746822 - 5.9619293
Average (Standard dev.)-0.0020097666 (±0.10063231)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 272.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_60388_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_60388_half_map_2.map
Projections & Slices
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Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Human high-affinity choline transporter CHT1 bound to choline und...

EntireName: Human high-affinity choline transporter CHT1 bound to choline under NaCl condition, with sodium and chloride ions coordinated.
Components
  • Complex: Human high-affinity choline transporter CHT1 bound to choline under NaCl condition, with sodium and chloride ions coordinated.
    • Protein or peptide: High affinity choline transporter 1
  • Ligand: CHOLINE ION
  • Ligand: SODIUM ION
  • Ligand: CHLORIDE ION

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Supramolecule #1: Human high-affinity choline transporter CHT1 bound to choline und...

SupramoleculeName: Human high-affinity choline transporter CHT1 bound to choline under NaCl condition, with sodium and chloride ions coordinated.
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: High affinity choline transporter 1

MacromoleculeName: High affinity choline transporter 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 63.239145 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAFHVEGLIA IIVFYLLILL VGIWAAWRTK NSGSAEERSE AIIVGGRDIG LLVGGFTMTA TWVGGGYING TAEAVYVPGY GLAWAQAPI GYSLSLILGG LFFAKPMRSK GYVTMLDPFQ QIYGKRMGGL LFIPALMGEM FWAAAIFSAL GATISVIIDV D MHISVIIS ...String:
MAFHVEGLIA IIVFYLLILL VGIWAAWRTK NSGSAEERSE AIIVGGRDIG LLVGGFTMTA TWVGGGYING TAEAVYVPGY GLAWAQAPI GYSLSLILGG LFFAKPMRSK GYVTMLDPFQ QIYGKRMGGL LFIPALMGEM FWAAAIFSAL GATISVIIDV D MHISVIIS ALIATLYTLV GGLYSVAYTD VVQLFCIFVG LWISVPFALS HPAVADIGFT AVHAKYQKPW LGTVDSSEVY SW LDSFLLL MLGGIPWQAY FQRVLSSSSA TYAQVLSFLA AFGCLVMAIP AILIGAIGAS TDWNQTAYGL PDPKTTEEAD MIL PIVLQY LCPVYISFFG LGAVSAAVMS SADSSILSAS SMFARNIYQL SFRQNASDKE IVWVMRITVF VFGASATAMA LLTK TVYGL WYLSSDLVYI VIFPQLLCVL FVKGTNTYGA VAGYVSGLFL RITGGEPYLY LQPLIFYPGY YPDDNGIYNQ KFPFK TLAM VTSFLTNICI SYLAKYLFES GTLPPKLDVF DAVVARHSEE NMDKTILVKN ENIKLDELAL VKPRQSMTLS STFTNK EAF LDVDSSPEGS GTEDNLQ

UniProtKB: High affinity choline transporter 1

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Macromolecule #3: CHOLINE ION

MacromoleculeName: CHOLINE ION / type: ligand / ID: 3 / Number of copies: 1 / Formula: CHT
Molecular weightTheoretical: 104.171 Da
Chemical component information

ChemComp-CHT:
CHOLINE ION

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Macromolecule #4: SODIUM ION

MacromoleculeName: SODIUM ION / type: ligand / ID: 4 / Number of copies: 1
Molecular weightTheoretical: 22.99 Da

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Macromolecule #5: CHLORIDE ION

MacromoleculeName: CHLORIDE ION / type: ligand / ID: 5 / Number of copies: 1 / Formula: CL
Molecular weightTheoretical: 35.453 Da

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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

Concentration10 mg/mL
BufferpH: 7.5
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV
DetailsThis sample was obtained from the monodispersed peak fractions of the size-exclusion chromatography.

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Electron microscopy

MicroscopeFEI TITAN 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

Startup modelType of model: INSILICO MODEL
In silico model: The insilico model was generated using the ab-initio reconstruction in cryoSPARC.
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 168876
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final 3D classificationNumber classes: 3 / Software - Name: cryoSPARC

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Atomic model buiding 1

RefinementProtocol: AB INITIO MODEL
Output model

PDB-8zqq:
Human high-affinity choline transporter CHT1 bound to choline under NaCl condition, with sodium and chloride ions coordinated.

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