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- PDB-9pmd: Human OCTN2 in an inward-facing conformation -

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Basic information

Entry
Database: PDB / ID: 9pmd
TitleHuman OCTN2 in an inward-facing conformation
ComponentsOrganic cation/carnitine transporter 2
KeywordsTRANSPORT PROTEIN / transporter / carnitine transporter / organic cation transporter / SLC22 family / sodium-dependent transport / membrane protein / solute carrier / metabolic transport / fatty acid oxidation / OCTN2 / SLC22A5
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.99 Å
AuthorsDavies, J.S. / Zeng, Y.Z. / Stewart, A.G.
Funding support Australia, 1items
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 17, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 3, 2025Provider: repository / Type: Initial release
Revision 1.0Dec 3, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Dec 3, 2025Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Dec 3, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Dec 3, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Dec 3, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
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Revision 1.1Dec 10, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.2Jan 21, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.1Jan 21, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
Data content type: EM metadata / EM metadata ...EM metadata / EM metadata / EM metadata / EM metadata / EM metadata
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Organic cation/carnitine transporter 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,2762
Polymers64,2531
Non-polymers231
Water362
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Organic cation/carnitine transporter 2 / High-affinity sodium-dependent carnitine cotransporter / Solute carrier family 22 member 5


Mass: 64252.977 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC22A5, OCTN2 / Cell line (production host): HEK-293F / Production host: Homo sapiens (human) / References: UniProt: O76082
#2: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: H2O
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: Novel organic cation transport 2 (OCTN2;SLC22A5) in an inward-facing conformation
Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293-F / Plasmid: pEG BacMam
Buffer solutionpH: 8 / Details: Size-exclusion buffer
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMTrisC4H11NO31
2150 mMSodium chlorideNaCl1
30.2 mMGlyco-diosgeninC56H92O251
410 mMCarnitineC7H15NO31
SpecimenConc.: 3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: The sample was monodisperse after size-exclusion chromatography
Specimen supportDetails: Pelco EasyGlow 15 mA / Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R0./1
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 295.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 500 nm / Cs: 2.7 mm
Image recordingElectron dose: 81 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 25 eV

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.6particle selection
2EPU2.14image acquisition
7ISOLDE1.8model fitting
8Coot0.9.8.94model fitting
10PHENIX1.21.1_5286model refinement
11cryoSPARC4.6initial Euler assignment
12cryoSPARC4.6final Euler assignment
13cryoSPARC4.6classification
14cryoSPARC4.63D reconstruction
CTF correctionType: PHASE FLIPPING ONLY
Particle selectionNum. of particles selected: 8480000
3D reconstructionResolution: 2.99 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 94746 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT
Atomic model buildingAccession code: O76082 / Source name: AlphaFold / Type: in silico model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0024302
ELECTRON MICROSCOPYf_angle_d0.5645857
ELECTRON MICROSCOPYf_dihedral_angle_d3.103575
ELECTRON MICROSCOPYf_chiral_restr0.039673
ELECTRON MICROSCOPYf_plane_restr0.007726

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