2. Academic Validation
  3. Structure and mechanism of the human bile acid transporter OSTα-OSTβ

Structure and mechanism of the human bile acid transporter OSTα-OSTβ

  • Nature. 2026 Mar;651(8104):251-259. doi: 10.1038/s41586-025-09934-8.
Ke Wang # 1 2 3,  Junping Fan # 4,  Huiwen Chen # 1,  Bo Huang # 5 6,  Cheng Chi # 7,  Rui Yan 1,  Di Wu 1 8,  Feng Zhou 6,  Wenhua Zhang 3,  Juquan Jiang 9,  Xiaoguang Lei 10,  Daohua Jiang 11 12
Affiliations

Affiliations

  • 1 Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing, China.
  • 2 Department of Microbiology and Biotechnology, College of Life Sciences, Northeast Agricultural University, Harbin, China.
  • 3 Jiangxi Institute of Respiratory Disease, First Affiliated Hospital; School of Basic Medical Sciences; Institute of Biomedical Innovation, Jiangxi Province Key Laboratory of Brain Science and Brain Health, Jiangxi Medical College, Nanchang University, Nanchang, China.
  • 4 Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China. [email protected].
  • 5 Department of Medicinal Chemistry, College of Pharmaceutical Sciences of Capital Medical University, Beijing, China.
  • 6 Beijing StoneWise Technology, Beijing, China.
  • 7 Peking University Institute of Advanced Agricultural Sciences, Shandong Laboratory of Advanced Agricultural Sciences at Weifang, Weifang, China.
  • 8 University of Chinese Academy of Sciences, Beijing, China.
  • 9 Department of Microbiology and Biotechnology, College of Life Sciences, Northeast Agricultural University, Harbin, China. [email protected].
  • 10 Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China. [email protected].
  • 11 Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing, China. [email protected].
  • 12 University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 41606314 DOI: 10.1038/s41586-025-09934-8
Abstract

Bile acids (BAs) are crucial amphipathic Surfactants that function as multifaceted regulators in various physiological processes, including nutrient absorption and distribution, lipid metabolism and inflammation1,2. The human organic solute transporter αβ (OSTα-OSTβ; hereafter referred to as OSTα/β) is a BA transporter that has a key role in the secretion and distribution of BAs3-6. Pathogenic mutations in OSTα/β have been associated with cholestasis7,8. Despite the functional importance of OSTα/β in BA homeostasis, the stoichiometry and assembly of the complex and the molecular mechanism that underlies BA transport by OSTα/β remain unknown. Here we present cryo-electron microscopy structures of human OSTα/β in complex with cholesterols and an endogenous substrate, elucidating the structural basis for the function of OSTα/β. OSTα/β is assembled in a novel dimer-of-heterodimers manner: two OSTα units form the homodimeric core, with two OSTβ units bound to the periphery. OSTα adopts the G-protein-coupled-receptor (GPCR) fold and contains a unique cysteine-rich loop with seven palmitoylation sites; these cooperate with transmembrane helices 5 and 6, constituting a BA recognition site. A positive cavity in OSTα connects the BA site and facilitates the transmembrane translocation of BAs through OSTα/β. Together, this study reveals the architecture and transport mechanism of OSTα/β and provides insights into the structure-function relationships of this crucial transporter in BA homeostasis.

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