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TitleStructural basis of sodium ion-dependent carnitine transport by OCTN2.
Journal, issue, pagesNat Commun, Vol. 17, Issue 1, Page 181, Year 2025
Publish dateNov 29, 2025
AuthorsJames S Davies / Yi C Zeng / Chelsea Briot / Simon H J Brown / Renae M Ryan / Alastair G Stewart /
PubMed AbstractCarnitine 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.
External linksNat Commun / PubMed:41318751 / PubMed Central
MethodsEM (single particle)
Resolution2.72 - 3.06 Å
Structure data

EMDB-71540, PDB-9pdq:
Human OCTN2 bound to carnitine in the occluded conformation
Method: EM (single particle) / Resolution: 2.72 Å

EMDB-71597, PDB-9pfb:
Human OCTN2 bound to ipratropium in an inward-facing conformation
Method: EM (single particle) / Resolution: 3.06 Å

EMDB-71735, PDB-9pmd:
Human OCTN2 in an inward-facing conformation
Method: EM (single particle) / Resolution: 2.99 Å

Chemicals

ChemComp-NA:
Unknown entry

ChemComp-152:
CARNITINE

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-HOH:
WATER

ChemComp-X8M:
IPRATROPIUM / medication*YM

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / transporter / carnitine transporter / organic cation transporter / SLC22 family / sodium-dependent transport / membrane protein / solute carrier / metabolic transport / fatty acid oxidation / OCTN2 / SLC22A5 / ipratropium / inhibitor

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