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- EMDB-64853: membrane protein S6A8 with RGX -

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Basic information

Entry
Database: EMDB / ID: EMD-64853
Titlemembrane protein S6A8 with RGX
Map data
Sample
  • Organelle or cellular component: membrane protein S6A8
    • Protein or peptide: Sodium- and chloride-dependent creatine transporter 1
  • Ligand: CHLORIDE ION
  • Ligand: Ompenaclid
  • Ligand: SODIUM ION
  • Ligand: water
Keywordsmembrane protein S6A8 / MEMBRANE PROTEIN
Function / homology
Function and homology information


creatine transmembrane transporter activity / creatine:sodium symporter activity / creatine transmembrane transport / creatine metabolic process / Creatine metabolism / gamma-aminobutyric acid:sodium:chloride symporter activity / neurotransmitter transport / amino acid transport / muscle contraction / sodium ion transmembrane transport ...creatine transmembrane transporter activity / creatine:sodium symporter activity / creatine transmembrane transport / creatine metabolic process / Creatine metabolism / gamma-aminobutyric acid:sodium:chloride symporter activity / neurotransmitter transport / amino acid transport / muscle contraction / sodium ion transmembrane transport / apical plasma membrane / membrane / plasma membrane
Similarity search - Function
Sodium:neurotransmitter symporter, creatine / 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 creatine transporter 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.75 Å
AuthorsZhang SS
Funding support China, 1 items
OrganizationGrant numberCountry
National Science Foundation (NSF, China)21532004, 31570733 China
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: Structural insights into the substrate uptake and inhibition of the human creatine transporter (hCRT).
Authors: Xinyi Yuan / Jian Yin / Chang Liu / Xudong Chen / Meiying Chen / Yixue Wang / Zi Yang / Yue Wang / Li Jiang / Niyun Zhou / Xiaojuan Wang / Botong Liu / Zhaoqi Ma / Kaiyan Wang / Hongen Li / ...Authors: Xinyi Yuan / Jian Yin / Chang Liu / Xudong Chen / Meiying Chen / Yixue Wang / Zi Yang / Yue Wang / Li Jiang / Niyun Zhou / Xiaojuan Wang / Botong Liu / Zhaoqi Ma / Kaiyan Wang / Hongen Li / Sensen Zhang / Yongfeng Shang / Maojun Yang /
Abstract: Creatine plays a vital role in cellular energy production and adenosine triphosphate (ATP) homeostasis and has also been identified as a neurotransmitter in the mammalian brain. Creatine is ...Creatine plays a vital role in cellular energy production and adenosine triphosphate (ATP) homeostasis and has also been identified as a neurotransmitter in the mammalian brain. Creatine is transported into cells by the human creatine transporter (hCRT) (SLC6A8), an Na/Cl-dependent symporter encoded on the X chromosome. Mutations in hCRT cause cerebral creatine deficiency syndrome 1, a neurological disorder marked by intellectual disability, speech delay, and seizures. Beyond its role in the brain and muscle, hCRT is highly expressed in metabolically active tumors. Many cancer cells, including colorectal cancer and glioblastoma, upregulate hCRT to sustain intracellular creatine levels and buffer ATP under energy stress. Pharmacological blockade of hCRT by RGX202 has been shown to impair tumor growth by disrupting energy homeostasis. Here, we report the high-resolution cryo-Electron Microscopy (cryo-EM) structures of human hCRT in three states: apo, creatine-bound, and RGX202-bound. hCRT adopts a canonical LeuT-fold with 12 transmembrane helices and two pseudosymmetric inverted repeats. Creatine is coordinated in the central substrate-binding site through interactions with transmembrane helices TM1, TM3, TM6, and TM8, while the inhibitor RGX202 occupies the same binding pocket, engaging in overlapping contacts that competitively block creatine access. Our structural and mechanistic findings clarify substrate recognition and inhibitory binding of hCRT, providing a molecular rationale for targeting hCRT in both inherited metabolic diseases and cancer therapy.
History
DepositionMay 30, 2025-
Header (metadata) releaseApr 15, 2026-
Map releaseApr 15, 2026-
UpdateApr 15, 2026-
Current statusApr 15, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_64853.png

Downloads & links

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Map

FileDownload / File: emd_64853.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 256 pix.
= 215.885 Å		0.84 Å/pix.
x 256 pix.
= 215.885 Å		0.84 Å/pix.
x 256 pix.
= 215.885 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8433 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.275
Minimum - Maximum-2.401782 - 3.3603883
Average (Standard dev.)-0.0021436373 (±0.085544005)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 215.8848 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_64853_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_64853_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : membrane protein S6A8

EntireName: membrane protein S6A8
Components
  • Organelle or cellular component: membrane protein S6A8
    • Protein or peptide: Sodium- and chloride-dependent creatine transporter 1
  • Ligand: CHLORIDE ION
  • Ligand: Ompenaclid
  • Ligand: SODIUM ION
  • Ligand: water

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Supramolecule #1: membrane protein S6A8

SupramoleculeName: membrane protein S6A8 / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Sodium- and chloride-dependent creatine transporter 1

MacromoleculeName: Sodium- and chloride-dependent creatine transporter 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 70.568336 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAKKSAENGI YSVSGDEKKG PLIAPGPDGA PAKGDGPVGL GTPGGRLAVP PRETWTRQMD FIMSCVGFAV GLGNVWRFPY LCYKNGGGV FLIPYVLIAL VGGIPIFFLE ISLGQFMKAG SINVWNICPL FKGLGYASMV IVFYCNTYYI MVLAWGFYYL V KSFTTTLP ...String:
MAKKSAENGI YSVSGDEKKG PLIAPGPDGA PAKGDGPVGL GTPGGRLAVP PRETWTRQMD FIMSCVGFAV GLGNVWRFPY LCYKNGGGV FLIPYVLIAL VGGIPIFFLE ISLGQFMKAG SINVWNICPL FKGLGYASMV IVFYCNTYYI MVLAWGFYYL V KSFTTTLP WATCGHTWNT PDCVEIFRHE DCANASLANL TCDQLADRRS PVIEFWENKV LRLSGGLEVP GALNWEVTLC LL ACWVLVY FCVWKGVKST GKIVYFTATF PYVVLVVLLV RGVLLPGALD GIIYYLKPDW SKLGSPQVWI DAGTQIFFSY AIG LGALTA LGSYNRFNNN CYKDAIILAL INSGTSFFAG FVVFSILGFM AAEQGVHISK VAESGPGLAF IAYPRAVTLM PVAP LWAAL FFFMLLLLGL DSQFVGVEGF ITGLLDLLPA SYYFRFQREI SVALCCALCF VIDLSMVTDG GMYVFQLFDY YSASG TTLL WQAFWECVVV AWVYGADRFM DDIACMIGYR PCPWMKWCWS FFTPLVCMGI FIFNVVYYEP LVYNNTYVYP WWGEAM GWA FALSSMLCVP LHLLGCLLRA KGTMAERWQH LTQPIWGLHH LEYRAQDADV RGLTTLTPVS ESSKVVVVES VM

UniProtKB: Sodium- and chloride-dependent creatine transporter 1

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Macromolecule #2: CHLORIDE ION

MacromoleculeName: CHLORIDE ION / type: ligand / ID: 2 / Number of copies: 1 / Formula: CL
Molecular weightTheoretical: 35.453 Da

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Macromolecule #3: Ompenaclid

MacromoleculeName: Ompenaclid / type: ligand / ID: 3 / Number of copies: 1 / Formula: A1D9S
Molecular weightTheoretical: 131.133 Da

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Macromolecule #4: SODIUM ION

MacromoleculeName: SODIUM ION / type: ligand / ID: 4 / Number of copies: 2
Molecular weightTheoretical: 22.99 Da

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Macromolecule #5: water

MacromoleculeName: water / type: ligand / ID: 5 / Number of copies: 10 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOCONTINUUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.75 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 175122
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: RANDOM ASSIGNMENT

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