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- EMDB-71597: Human OCTN2 bound to ipratropium in an inward-facing conformation -

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Basic information

Entry
Database: EMDB / ID: EMD-71597
TitleHuman OCTN2 bound to ipratropium in an inward-facing conformation
Map dataPrimary unsharpened map. Has strong density for ipratropium in substrate-binding site.
Sample
  • Organelle or cellular component: Novel organic cation transport 2 (OCTN2;SLC22A5) bound to ipratropium in an inward-facing conformation
    • Protein or peptide: Organic cation/carnitine transporter 2
  • Ligand: IPRATROPIUM
  • Ligand: SODIUM ION
Keywordstransporter / carnitine transporter / organic cation transporter / SLC22 family / sodium-dependent transport / membrane protein / solute carrier / metabolic transport / fatty acid oxidation / OCTN2 / SLC22A5 / ipratropium / inhibitor / TRANSPORT PROTEIN
Function / homology
Function and homology information


positive regulation of intestinal epithelial structure maintenance / sodium-dependent organic cation transport / (R)-carnitine transport / (R)-carnitine transmembrane transport / Defective SLC22A5 causes systemic primary carnitine deficiency (CDSP) / carnitine transport / carnitine transmembrane transport / carnitine transmembrane transporter activity / (R)-carnitine transmembrane transporter activity / quaternary ammonium group transmembrane transporter activity ...positive regulation of intestinal epithelial structure maintenance / sodium-dependent organic cation transport / (R)-carnitine transport / (R)-carnitine transmembrane transport / Defective SLC22A5 causes systemic primary carnitine deficiency (CDSP) / carnitine transport / carnitine transmembrane transport / carnitine transmembrane transporter activity / (R)-carnitine transmembrane transporter activity / quaternary ammonium group transmembrane transporter activity / amino-acid betaine transmembrane transporter activity / SLC-mediated transport of organic cations / quaternary ammonium group transport / response to symbiotic bacterium / Carnitine shuttle / xenobiotic detoxification by transmembrane export across the plasma membrane / symporter activity / sodium ion transport / response to tumor necrosis factor / xenobiotic transmembrane transporter activity / response to type II interferon / transport across blood-brain barrier / basal plasma membrane / PDZ domain binding / brush border membrane / apical plasma membrane / endoplasmic reticulum / extracellular exosome / ATP binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Solute carrier family 22 members 4/5 / Organic cation transport protein/SVOP / Sugar transport proteins signature 1. / Sugar transporter, conserved site / Major facilitator, sugar transporter-like / Sugar (and other) transporter / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / MFS transporter superfamily
Similarity search - Domain/homology
Organic cation/carnitine transporter 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.06 Å
AuthorsDavies JS / Zeng YZ / Stewart AG
Funding support Australia, 1 items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia)APP2016308 Australia
CitationJournal: Nat Commun / Year: 2025
Title: Structural basis of sodium ion-dependent carnitine transport by OCTN2.
Authors: James S Davies / Yi C Zeng / Chelsea Briot / Simon H J Brown / Renae M Ryan / Alastair G Stewart /
Abstract: Carnitine is essential for the import of long-chain fatty acids into mitochondria, where they are used for energy production. The carnitine transporter OCTN2 (novel organic cation transporter 2, ...Carnitine is essential for the import of long-chain fatty acids into mitochondria, where they are used for energy production. The carnitine transporter OCTN2 (novel organic cation transporter 2, SLC22A5) mediates carnitine uptake across the plasma membrane and as such facilitates fatty acid metabolism in most tissues. OCTN2 dysfunction causes systemic primary carnitine deficiency (SPCD), a potentially lethal disorder. Despite its importance in metabolism, the mechanism of high-affinity, sodium ion-dependent transport by OCTN2 is unclear. Here we report cryo-EM structures of human OCTN2 in three conformations: inward-facing ligand-free, occluded carnitine- and Na-bound, and inward-facing ipratropium-bound. These structures define key interactions responsible for carnitine transport and identify an allosterically coupled Na binding site housed within an aqueous cavity, separate from the carnitine-binding site. Combined with electrophysiology data, we provide a framework for understanding variants associated with SPCD and insight into how OCTN2 functions as the primary human carnitine transporter.
History
DepositionJul 3, 2025-
Header (metadata) releaseDec 3, 2025-
Map releaseDec 3, 2025-
UpdateJan 21, 2026-
Current statusJan 21, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_71597.png

Downloads & links

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Map

FileDownload / File: emd_71597.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationPrimary unsharpened map. Has strong density for ipratropium in substrate-binding site.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 320 pix.
= 265.6 Å		0.83 Å/pix.
x 320 pix.
= 265.6 Å		0.83 Å/pix.
x 320 pix.
= 265.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0822
Minimum - Maximum-0.21115819 - 0.46722603
Average (Standard dev.)0.00033586458 (±0.010959395)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 265.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Cryosparc sharpened map (B-factor 101). Weak density at...

Fileemd_71597_additional_1.map
AnnotationCryosparc sharpened map (B-factor 101). Weak density at Na site indicates partial occupancy.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half-map A.

Fileemd_71597_half_map_1.map
AnnotationHalf-map A.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half-map B.

Fileemd_71597_half_map_2.map
AnnotationHalf-map B.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Novel organic cation transport 2 (OCTN2;SLC22A5) bound to ipratro...

EntireName: Novel organic cation transport 2 (OCTN2;SLC22A5) bound to ipratropium in an inward-facing conformation
Components
  • Organelle or cellular component: Novel organic cation transport 2 (OCTN2;SLC22A5) bound to ipratropium in an inward-facing conformation
    • Protein or peptide: Organic cation/carnitine transporter 2
  • Ligand: IPRATROPIUM
  • Ligand: SODIUM ION

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Supramolecule #1: Novel organic cation transport 2 (OCTN2;SLC22A5) bound to ipratro...

SupramoleculeName: Novel organic cation transport 2 (OCTN2;SLC22A5) bound to ipratropium in an inward-facing conformation
type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Organic cation/carnitine transporter 2

MacromoleculeName: Organic cation/carnitine transporter 2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 64.252977 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MRDYDEVTAF LGEWGPFQRL IFFLLSASII PNGFTGLSSV FLIATPEHRC RVPDAANLSS AWRNHTVPLR LRDGREVPHS CRRYRLATI ANFSALGLEP GRDVDLGQLE QESCLDGWEF SQDVYLSTIV TEWNLVCEDD WKAPLTISLF FVGVLLGSFI S GQLSDRFG ...String:
MRDYDEVTAF LGEWGPFQRL IFFLLSASII PNGFTGLSSV FLIATPEHRC RVPDAANLSS AWRNHTVPLR LRDGREVPHS CRRYRLATI ANFSALGLEP GRDVDLGQLE QESCLDGWEF SQDVYLSTIV TEWNLVCEDD WKAPLTISLF FVGVLLGSFI S GQLSDRFG RKNVLFVTMG MQTGFSFLQI FSKNFEMFVV LFVLVGMGQI SNYVAAFVLG TEILGKSVRI IFSTLGVCIF YA FGYMVLP LFAYFIRDWR MLLVALTMPG VLCVALWWFI PESPRWLISQ GRFEEAEVII RKAAKANGIV VPSTIFDPSE LQD LSSKKQ QSHNILDLLR TWNIRMVTIM SIMLWMTISV GYFGLSLDTP NLHGDIFVNC FLSAMVEVPA YVLAWLLLQY LPRR YSMAT ALFLGGSVLL FMQLVPPDLY YLATVLVMVG KFGVTAAFSM VYVYTAELYP TVVRNMGVGV SSTASRLGSI LSPYF VYLG AYDRFLPYIL MGSLTILTAI LTLFLPESFG TPLPDTIDQM LRVKGMKHRK TPSHTRMLKD GQERPTILKS TAFGAA FES RLEVLFQ

UniProtKB: Organic cation/carnitine transporter 2

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Macromolecule #2: IPRATROPIUM

MacromoleculeName: IPRATROPIUM / type: ligand / ID: 2 / Number of copies: 1 / Formula: X8M
Molecular weightTheoretical: 332.457 Da
Chemical component information

ChemComp-X8M:
IPRATROPIUM / medication*YM

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Macromolecule #3: SODIUM ION

MacromoleculeName: SODIUM ION / type: ligand / ID: 3 / Number of copies: 1
Molecular weightTheoretical: 22.99 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

Concentration3 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
20.0 mMC4H11NO3Tris
150.0 mMNaClSodium chloride
0.2 mMC56H92O25Glyco-diosgenin
1.0 mMC20H30BrNO3Ipratropium bromide
0.5 %C2H6OSDMSO
GridModel: UltrAuFoil / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY ARRAY / Support film - Film thickness: 50
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 295.15 K / Instrument: FEI VITROBOT MARK IV
DetailsThe sample was monodisperse after size-exclusion chromatography

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 79.0 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: 1.5 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 10039027
CTF correctionType: PHASE FLIPPING ONLY
Startup modelType of model: NONE / Details: Ab initio reconstruction
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.06 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.6.0) / Number images used: 382921
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final 3D classificationNumber classes: 5
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

6082


Chain - Source name: AlphaFold / Chain - Initial model type: in silico model
RefinementProtocol: FLEXIBLE FIT
Output model

PDB-9pfb:
Human OCTN2 bound to ipratropium in an inward-facing conformation

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