2. Academic Validation
  3. Structures of Ostα/β reveal a unique fold and bile acid transport mechanism

Structures of Ostα/β reveal a unique fold and bile acid transport mechanism

  • Nature. 2026 Mar;651(8104):260-267. doi: 10.1038/s41586-025-10029-7.
Xuemei Yang # 1,  Nana Cui # 2,  Tianyu Li # 3 4,  Xinheng He # 3 4,  Heng Zhang 3,  Canrong Wu 1,  Yang Li 3 4,  Xiong Ma 5 6,  H Eric Xu 7 8 9
Affiliations

Affiliations

  • 1 Research Center for Medicinal Structural Biology, National Research Center for Translational Medicine at Shanghai, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, NHC Key Laboratory of Digestive Diseases, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China.
  • 3 The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 4 University of Chinese Academy of Sciences, Beijing, China.
  • 5 Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, NHC Key Laboratory of Digestive Diseases, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China. [email protected].
  • 6 Institute of Aging and Tissue Regeneration, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 7 Research Center for Medicinal Structural Biology, National Research Center for Translational Medicine at Shanghai, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 8 The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 9 The Shanghai Advanced Electron Microscope Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 41606328 DOI: 10.1038/s41586-025-10029-7
Abstract

Bile acid and steroid hormone homeostasis are critical for human health, with disruptions linked to metabolic and endocrine disorders1,2. The organic solute transporter Ostα/β, essential for bile acid efflux in enterohepatic circulation3, has long defied mechanistic elucidation. Here we present cryogenic electron microscopy structures of human Ostα/β in apo and substrate-bound states at 2.6-3.1 Å resolution, revealing a distinctive membrane protein architecture that defines a new transporter class. Ostα/β forms a symmetric tetramer of heterodimers, with each Ostα subunit showing a new seven-transmembrane fold, augmented by a single transmembrane helix of Ostβ. This architecture is stabilized by extensive lipid modifications, including a palmitoylated cysteine-rich motif that forms a lateral substrate-binding groove. The structures uncover a unique transport pathway featuring two substrate-binding sites connected by an amphipathic helix-gated conduit. This design, conserved in the evolutionarily related TMEM184 family, suggests an ancient mechanism for substrate translocation. Electrophysiological studies demonstrate voltage-sensitive, bidirectional transport driven by electrochemical gradients, elucidating the efflux role of Ostα/β in vivo. Lipid interactions, notably palmitoylation-dependent trafficking, emerge as critical for stability and function. These findings clarify the molecular mechanism of Ostα/β, provide a structural basis for disease-associated mutations4,5 and establish a paradigm for lipid-modified membrane transport.

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