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<p>Mammalian organic solute transporter α/β (OSTα/β) is crucial for the enterohepatic circulation of bile acids and the homeostasis of steroid conjugates, mediating their movement across membranes as an obligate heterodimer. Here we present high-resolution cryo-EM structures of human OSTα/β in apo, substrate-bound and inhibitor-bound states, revealing a tetrameric organization as a homodimer of heterodimers that is required for membrane activity. Substrates bind within a surface-exposed tunnel formed by transmembrane helices 5 and 6, which is unexpectedly sealed by multiple palmitoyl chains covalently attached to a conserved intracellular loop IL2. Two chemically distinct inhibitors, fidaxomicin and ethinylestradiol, disrupt transport by both competing for the substrate-binding pocket and sterically occluding the tunnel. Together with biochemical and evolutionary analyses, our work defines a distinctive class of solute carriers that uses palmitoylation to facilitate substrate transport, a mechanism conserved across eukaryotes.</p>

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Structural insights into OSTα/β-mediated transport of bile acids and steroid conjugates

  • 期刊论文

  • 发表日期：

    2026年6月16日

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  • Xicheng Sun,
  • Taikun Tian,
  • Minying Low,
  • Shaobai Li,
  • Deqiang Yao,
  • Yanmei Yuan,
  • Mi Cao,
  • Ming Lei,
  • Yong Wang,
  • Hongwen Chen,
  • Pengfei Lan,
  • Qiang Xia,
  • Jing Xue

摘要

Mammalian organic solute transporter α/β (OSTα/β) is crucial for the enterohepatic circulation of bile acids and the homeostasis of steroid conjugates, mediating their movement across membranes as an obligate heterodimer. Here we present high-resolution cryo-EM structures of human OSTα/β in apo, substrate-bound and inhibitor-bound states, revealing a tetrameric organization as a homodimer of heterodimers that is required for membrane activity. Substrates bind within a surface-exposed tunnel formed by transmembrane helices 5 and 6, which is unexpectedly sealed by multiple palmitoyl chains covalently attached to a conserved intracellular loop IL2. Two chemically distinct inhibitors, fidaxomicin and ethinylestradiol, disrupt transport by both competing for the substrate-binding pocket and sterically occluding the tunnel. Together with biochemical and evolutionary analyses, our work defines a distinctive class of solute carriers that uses palmitoylation to facilitate substrate transport, a mechanism conserved across eukaryotes.