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Structure of the bile acid transporter and HBV receptor NTCP

Author

Listed:
  • Jinta Asami

    (The University of Tokyo)

  • Kanako Terakado Kimura

    (Kyoto University)

  • Yoko Fujita-Fujiharu

    (Kyoto University
    Kyoto University
    CREST, Japan Science and Technology Agency)

  • Hanako Ishida

    (The University of Tokyo)

  • Zhikuan Zhang

    (The University of Tokyo)

  • Yayoi Nomura

    (Kyoto University)

  • Kehong Liu

    (Kyoto University)

  • Tomoko Uemura

    (Kyoto University)

  • Yumi Sato

    (Kyoto University)

  • Masatsugu Ono

    (Kyoto University)

  • Masaki Yamamoto

    (RIKEN SPring-8 Center)

  • Takeshi Noda

    (Kyoto University
    Kyoto University
    CREST, Japan Science and Technology Agency)

  • Hideki Shigematsu

    (RIKEN SPring-8 Center)

  • David Drew

    (Stockholm University)

  • So Iwata

    (Kyoto University
    RIKEN SPring-8 Center)

  • Toshiyuki Shimizu

    (The University of Tokyo)

  • Norimichi Nomura

    (Kyoto University)

  • Umeharu Ohto

    (The University of Tokyo)

Abstract

Chronic infection with hepatitis B virus (HBV) affects more than 290 million people worldwide, is a major cause of cirrhosis and hepatocellular carcinoma, and results in an estimated 820,000 deaths annually1,2. For HBV infection to be established, a molecular interaction is required between the large glycoproteins of the virus envelope (known as LHBs) and the host entry receptor sodium taurocholate co-transporting polypeptide (NTCP), a sodium-dependent bile acid transporter from the blood to hepatocytes3. However, the molecular basis for the virus–transporter interaction is poorly understood. Here we report the cryo-electron microscopy structures of human, bovine and rat NTCPs in the apo state, which reveal the presence of a tunnel across the membrane and a possible transport route for the substrate. Moreover, the cryo-electron microscopy structure of human NTCP in the presence of the myristoylated preS1 domain of LHBs, together with mutation and transport assays, suggest a binding mode in which preS1 and the substrate compete for the extracellular opening of the tunnel in NTCP. Our preS1 domain interaction analysis enables a mechanistic interpretation of naturally occurring HBV-insusceptible mutations in human NTCP. Together, our findings provide a structural framework for HBV recognition and a mechanistic understanding of sodium-dependent bile acid translocation by mammalian NTCPs.

Suggested Citation

  • Jinta Asami & Kanako Terakado Kimura & Yoko Fujita-Fujiharu & Hanako Ishida & Zhikuan Zhang & Yayoi Nomura & Kehong Liu & Tomoko Uemura & Yumi Sato & Masatsugu Ono & Masaki Yamamoto & Takeshi Noda & H, 2022. "Structure of the bile acid transporter and HBV receptor NTCP," Nature, Nature, vol. 606(7916), pages 1021-1026, June.
  • Handle: RePEc:nat:nature:v:606:y:2022:i:7916:d:10.1038_s41586-022-04845-4
    DOI: 10.1038/s41586-022-04845-4
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    Cited by:

    1. 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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