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Structural basis of sodium-dependent bile salt uptake into the liver

Author

Listed:
  • Kapil Goutam

    (University of Bordeaux, CNRS-UMR5234
    Institut Pasteur)

  • Francesco S. Ielasi

    (Institut Pasteur)

  • Els Pardon

    (Vrije Universiteit Brussel, VUB
    VIB-VUB Center for Structural Biology, VIB)

  • Jan Steyaert

    (Vrije Universiteit Brussel, VUB
    VIB-VUB Center for Structural Biology, VIB)

  • Nicolas Reyes

    (University of Bordeaux, CNRS-UMR5234
    Institut Pasteur)

Abstract

The liver takes up bile salts from blood to generate bile, enabling absorption of lipophilic nutrients and excretion of metabolites and drugs1. Human Na+–taurocholate co-transporting polypeptide (NTCP) is the main bile salt uptake system in liver. NTCP is also the cellular entry receptor of human hepatitis B and D viruses2,3 (HBV/HDV), and has emerged as an important target for antiviral drugs4. However, the molecular mechanisms underlying NTCP transport and viral receptor functions remain incompletely understood. Here we present cryo-electron microscopy structures of human NTCP in complexes with nanobodies, revealing key conformations of its transport cycle. NTCP undergoes a conformational transition opening a wide transmembrane pore that serves as the transport pathway for bile salts, and exposes key determinant residues for HBV/HDV binding to the outside of the cell. A nanobody that stabilizes pore closure and inward-facing states impairs recognition of the HBV/HDV receptor-binding domain preS1, demonstrating binding selectivity of the viruses for open-to-outside over inward-facing conformations of the NTCP transport cycle. These results provide molecular insights into NTCP ‘gated-pore’ transport and HBV/HDV receptor recognition mechanisms, and are expected to help with development of liver disease therapies targeting NTCP.

Suggested Citation

  • Kapil Goutam & Francesco S. Ielasi & Els Pardon & Jan Steyaert & Nicolas Reyes, 2022. "Structural basis of sodium-dependent bile salt uptake into the liver," Nature, Nature, vol. 606(7916), pages 1015-1020, June.
  • Handle: RePEc:nat:nature:v:606:y:2022:i:7916:d:10.1038_s41586-022-04723-z
    DOI: 10.1038/s41586-022-04723-z
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    Cited by:

    1. Yongzhen Liu & Thomas R. Cafiero & Debby Park & Abhishek Biswas & Benjamin Y. Winer & Cheul H. Cho & Yaron Bram & Vasuretha Chandar & Aoife K. O’ Connell & Hans P. Gertje & Nicholas Crossland & Robert, 2023. "Targeted viral adaptation generates a simian-tropic hepatitis B virus that infects marmoset cells," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Kaho Shionoya & Jae-Hyun Park & Toru Ekimoto & Junko S. Takeuchi & Junki Mifune & Takeshi Morita & Naito Ishimoto & Haruka Umezawa & Kenichiro Yamamoto & Chisa Kobayashi & Atsuto Kusunoki & Norimichi , 2024. "Structural basis for hepatitis B virus restriction by a viral receptor homologue," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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