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Structural insights into the HBV receptor and bile acid transporter NTCP

Author

Listed:
  • Jae-Hyun Park

    (Yokohama City University)

  • Masashi Iwamoto

    (National Institute of Infectious Diseases)

  • Ji-Hye Yun

    (Yonsei University
    PCG-Biotech)

  • Tomomi Uchikubo-Kamo

    (RIKEN Center for Biosystems Dynamics Research)

  • Donghwan Son

    (Yonsei University)

  • Zeyu Jin

    (Yokohama City University
    Yonsei University)

  • Hisashi Yoshida

    (Yokohama City University)

  • Mio Ohki

    (Yokohama City University)

  • Naito Ishimoto

    (Yokohama City University)

  • Kenji Mizutani

    (Yokohama City University)

  • Mizuki Oshima

    (National Institute of Infectious Diseases
    Tokyo University of Science)

  • Masamichi Muramatsu

    (National Institute of Infectious Diseases)

  • Takaji Wakita

    (National Institute of Infectious Diseases)

  • Mikako Shirouzu

    (RIKEN Center for Biosystems Dynamics Research)

  • Kehong Liu

    (Kyoto University)

  • Tomoko Uemura

    (Kyoto University)

  • Norimichi Nomura

    (Kyoto University)

  • So Iwata

    (Kyoto University
    RIKEN SPring-8 Center)

  • Koichi Watashi

    (National Institute of Infectious Diseases
    Tokyo University of Science
    Research Center for Drug and Vaccine Development)

  • Jeremy R. H. Tame

    (Yokohama City University)

  • Tomohiro Nishizawa

    (Yokohama City University)

  • Weontae Lee

    (Yonsei University
    PCG-Biotech)

  • Sam-Yong Park

    (Yokohama City University)

Abstract

Around 250 million people are infected with hepatitis B virus (HBV) worldwide1, and 15 million may also carry the satellite virus hepatitis D virus (HDV), which confers even greater risk of severe liver disease2. The HBV receptor has been identified as sodium taurocholate co-transporting polypeptide (NTCP), which interacts directly with the first 48 amino acid residues of the N-myristoylated N-terminal preS1 domain of the viral large protein3. Despite the pressing need for therapeutic agents to counter HBV, the structure of NTCP remains unsolved. This 349-residue protein is closely related to human apical sodium-dependent bile acid transporter (ASBT), another member of the solute carrier family SLC10. Crystal structures have been reported of similar bile acid transporters from bacteria4,5, and these models are believed to resemble closely both NTCP and ASBT. Here we have used cryo-electron microscopy to solve the structure of NTCP bound to an antibody, clearly showing that the transporter has no equivalent of the first transmembrane helix found in other SLC10 proteins, and that the N terminus is exposed on the extracellular face. Comparison of our structure with those of related proteins indicates a common mechanism of bile acid transport, but the NTCP structure displays an additional pocket formed by residues that are known to interact with preS1, presenting new opportunities for structure-based drug design.

Suggested Citation

  • Jae-Hyun Park & Masashi Iwamoto & Ji-Hye Yun & Tomomi Uchikubo-Kamo & Donghwan Son & Zeyu Jin & Hisashi Yoshida & Mio Ohki & Naito Ishimoto & Kenji Mizutani & Mizuki Oshima & Masamichi Muramatsu & Tak, 2022. "Structural insights into the HBV receptor and bile acid transporter NTCP," Nature, Nature, vol. 606(7916), pages 1027-1031, June.
    • Handle: RePEc:nat:nature:v:606:y:2022:i:7916:d:10.1038_s41586-022-04857-0
    DOI: 10.1038/s41586-022-04857-0
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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.

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