9UO2

Cryo-EM structure of human organic solute transporter Ost-alpha/beta in apo state

Summary for 9UO2

• Entry DOI: 10.2210/pdb9uo2/pdb
• EMDB information: 64370
• Descriptor: Organic solute transporter subunit alpha, Organic solute transporter subunit beta, (7E,21R,24S)-27-amino-24-hydroxy-18,24-dioxo-19,23,25-trioxa-24lambda~5~-phosphaheptacos-7-en-21-yl (9Z,12E)-octadeca-9,12-dienoate, ... (8 entities in total)
• Functional Keywords: complex, bile acids, transport protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 133910.56

Authors

Yang, X.,Xu, E. (deposition date: 2025-04-24, release date: 2025-12-10, Last modification date: 2026-03-18)

Primary citation

Yang, X.,Cui, N.,Li, T.,He, X.,Zhang, H.,Wu, C.,Li, Y.,Ma, X.,Xu, H.E.
Structures of Ost alpha / beta reveal a unique fold and bile acid transport mechanism.
Nature, 651:260-267, 2026

PubMed Abstract: Bile acid and steroid hormone homeostasis are critical for human health, with disruptions linked to metabolic and endocrine disorders. The organic solute transporter Ostα/β, essential for bile acid efflux in enterohepatic circulation, 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 mutations and establish a paradigm for lipid-modified membrane transport.

PubMed: 41606328
DOI: 10.1038/s41586-025-10029-7

Experimental method

ELECTRON MICROSCOPY (2.6 Å)