Structure and mechanism of the human bile acid transporter OSTα–OSTβ
Article meta
Article Date: 28 January 2026
Article URL: https://www.nature.com/articles/s41586-025-09934-8
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Summary
This Nature study presents cryo-EM structures of the human heteromeric bile acid and steroid transporter OSTα–OSTβ in two states: with cholesteryl hemisuccinate (CHS) and bound to the steroid sulphate DHEAS. The authors combine structural biology, functional transport assays, FRET, thermostability tests and molecular dynamics (MD) to map the architecture, the α–β interface, a likely bile-acid binding pathway and conformational transitions that underpin transport. The work provides atomic models (PDB 9LJG and 9LJH; EMDB EMD-63148 and EMD-63149) and links structure to function with mutational and simulation validation.
Key Points
- The cryo-EM structures reveal OSTα adopts a seven-transmembrane-like fold partnered with a single-pass OSTβ subunit, producing a distinct heteromeric transporter architecture.
- Structures were solved in CHS and with DHEAS bound, identifying a putative bile-acid / steroid-binding region and lipid (cholesterol/CHS) interactions stabilising the complex.
- Biochemical assays (transport, TCA/DHEAS uptake), thermostability and FRET support the structural model and show specific residues and loops are important for activity and stability.
- MD and enhanced-sampling simulations demonstrate conformational flexibility and plausible substrate translocation pathways consistent with an alternating-access-like mechanism.
- Comparative analysis positions OSTα/β relative to other bile-acid transporters and GPCR-like 7TM proteins, highlighting unique features of the α–β interface and extracellular domain.
- Data and coordinates are publicly available: EMDB EMD-63148/63149 and PDB 9LJG/9LJH; supporting source data and extended figures accompany the paper.
Content summary
The authors expressed and purified human OSTα–OSTβ, collected cryo-EM data and obtained reconstructions for two biochemical states. The maps enabled model building of OSTα (multi-pass) and OSTβ (single-pass) and showed cholesterol-like molecules bound at specific sites. Functional tests (radioactive bile-acid uptake, substrate competition and mutational scans) identified residues that alter transport or thermostability, corroborating the binding pocket located between transmembrane helices and the extracellular domain.
The study uses GFP-based thermostability assays, FRET to probe subunit arrangements, MD and well-tempered metadynamics to explore conformational states and substrate movement. Structural comparisons to other bile-acid transporters and GPCR 7TM domains revealed both similarities and important differences—particularly in how OSTβ interacts with OSTα to enable trafficking and function. The authors discuss implications for bile-acid handling in intestine, kidney and liver and note links to human disease associated with OSTα/β dysfunction.
Context and relevance
OSTα–OSTβ is the major basolateral transporter for bile acids and conjugated steroids in several epithelia; defects or altered regulation are implicated in cholestasis, congenital diarrhoeas and liver disease (including NASH). High-resolution structures plus functional validation give a molecular map to interpret disease mutations, predict drug interactions and guide design of modulators or inhibitors that target bile-acid circulation.
This work sits alongside recent structural studies of other hepatic and intestinal transporters and advances our mechanistic understanding of how heteromeric membrane complexes move amphipathic substrates across bilayers. For pharmacology and hepatology, the findings are directly relevant to drug–transporter interactions, enterohepatic circulation modulation and therapeutic targeting of bile-acid pathways.
Author style
Punchy: the paper delivers a clear structural and mechanistic story tying atomic models to transport function. If you work on membrane transporters, liver biology or drug–transporter interactions, the details matter — these structures provide concrete hypotheses and residues to test.
Why should I read this?
Short version: it explains, in molecular detail, how the human OSTα–OSTβ duo carries bile acids and steroid-sulphates across cell basolateral membranes — and points to the exact spots where drugs or mutations might mess things up. Reads fast, gives you testable targets and saves you digging through decades of functional data.
Source
Source: https://www.nature.com/articles/s41586-025-09934-8
Data access
EMDB accessions: EMD-63148, EMD-63149. PDB codes: 9LJG (OSTα/β-CHS), 9LJH (OSTα/β-DHEAS). Additional source data available with the paper.