Structures of Ostα/β reveal a unique fold and bile acid transport mechanism
Article Date: 28 January 2026
Article URL: https://www.nature.com/articles/s41586-025-10029-7
Article Image: https://www.nature.com/articles/s41586-025-10029-7
Summary
Researchers solved cryo-EM structures of the human heteromeric organic solute transporter Ostα/β in multiple states (apo, TLCA-bound and DHEAS-bound) and report a previously unseen fold and transport mechanism. The study combines structural models, molecular dynamics (MD) simulations and functional assays to map ligand binding sites, lipid and cholesterol interactions, and a likely route for substrate translocation. Key regulatory features such as Ostα palmitoylation and lipid interfaces that stabilise the complex are described, and structural coordinates and maps are deposited (PDB and EMDB accessions listed in the paper).
Key Points
- Cryo-EM structures of Ostα/β solved in apo and ligand-bound states (EMD/PDB deposits provided in the article).
- Ostα/β adopts a unique fold distinct from previously characterised bile-acid transporters (not a typical MFS or sodium symporter fold).
- Specific extracellular and inner-lateral binding sites for bile-acid-like ligands (TLCA, DHEAS) were identified and validated by mutagenesis and uptake assays.
- Lipids and multiple cholesterol-like molecules bind at interfaces and stabilise the complex; mutations at lipid interfaces alter transport and membrane localisation.
- Palmitoylation of Ostα affects its subcellular localisation and transport activity, linking post-translational modification to function.
- MD simulations show upward movement of DHEAS in oligomeric assemblies, suggesting a stepwise translocation pathway.
- Functional data (radiolabel uptake, electrophysiology, FACS and co-immunoprecipitation) support the structural conclusions.
- Extensive data availability: maps, coordinates, MD files and supplementary materials are publicly archived (details in paper).
Content summary
The team purified human Ostα/β and determined cryo-EM reconstructions of heterodimeric and tetrameric assemblies in apo and ligand-bound forms. Comparison across states revealed only subtle global shifts but defined clear ligand pockets near the extracellular face and an inner cavity. Several cholesterol- and phospholipid-like densities were modelled at inter-subunit interfaces, and interface mutants showed altered transport or surface expression. Palmitoylation sites on Ostα were shown to regulate plasma membrane targeting and transport efficiency. MD simulations visualised ligand dynamics (notably DHEAS) moving upward through a putative pathway, supporting a non-classical transport mechanism distinct from sodium-driven symporters. The authors combine structural, biochemical and computational evidence to propose how Ostα/β mediates bile acid and steroid transport at the ileal basolateral membrane.
Context and relevance
OSTα/β (SLC51) is a key basolateral exporter of bile acids and steroid-derived molecules in intestinal, renal and biliary epithelia. Understanding its structure clarifies how bile acids are handled during enterohepatic circulation and why OST dysfunction links to cholestasis, congenital diarrhoea and liver disease. The new structural insight complements recent work on other bile-acid transporters (NTCP, ASBT) and points to unique pharmacological opportunities: targeting OSTα/β could modify bile-acid disposition, affect drug absorption and influence diseases such as nonalcoholic steatohepatitis (NASH) or cholestasis.
Why should I read this?
Fancy knowing how your gut cells hand bile acids back to the bloodstream? This paper shows the transporter in action, with pretty clear snapshots and simulations — and it explains why lipids and a tiny chemical tag (palmitoylation) make the whole machine work. If you care about bile-acid biology, drug transport, liver or gut disease, this saves you hours of digging: the mechanisms and PDB/EMD data are all here.
Author note (tone: punchy)
Punchy take: this is one of those structural papers that actually changes how you think about a transporter family. The fold is novel, the lipid interactions matter, and the functional follow‑ups are convincing. For structural biologists and translational teams working on bile acids or drug delivery, the details are worth diving into.