Structure of bile acid transporter NTCP crucial for hepatitis B virus entry - Nature.com

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Abstract

Chronic infection with hepatitis B virus (HBV), affecting more than 290 million people worldwide, is a major cause of cirrhosis and hepatocellular carcinoma and results in an estimated 820,000 human deaths annually^1,2. Establishment of HBV infection requires a molecular interaction between the virus envelope glycoprotein L (LHBs) and the host entry receptor sodium-taurocholate co-transporting polypeptide (NTCP), a sodium-dependent bile acid transporter from blood to hepatocytes ^3. However, the molecular basis for the virus-transporter interaction is poorly understood. Here, we report the cryo-electron microscopy (cryo-EM) structures of human, bovine, and rat NTCPs in the apo state, which reveals the presence of a tunnel across the membrane and a possible transport route for the substrate. Moreover, the cryo-EM structure of human NTCP in the presence of myristoylated preS1 domain of LHBs together with mutation and transport assays suggest a binding mode whereby preS1 and the substrate compete for the extracellular opening of the tunnel in NTCP. Importantly, the preS1 domain interaction analysis enables a mechanistic interpretation of naturally occurring HBV-insusceptible mutations in human NTCP. Taken together, our findings provide structural framework for HBV recognition and for mechanistic understanding of sodium-dependent bile acid translocation by mammalian NTCPs.

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These authors contributed equally: Jinta Asami, Kanako Terakado Kimura and Yoko Fujita-Fujiharu

Affiliations

Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan

Jinta Asami, Hanako Ishida, Zhikuan Zhang, Toshiyuki Shimizu & Umeharu Ohto
Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto, Japan

Kanako Terakado Kimura, Yayoi Nomura, Kehong Liu, Tomoko Uemura, Yumi Sato, Masatsugu Ono, So Iwata & Norimichi Nomura
Laboratory of Ultrastructural Virology, Institute for Frontier Life and Medical Sciences, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Japan

Yoko Fujita-Fujiharu & Takeshi Noda
Laboratory of Ultrastructural Virology, Graduate School of Biostudies, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Japan

Yoko Fujita-Fujiharu & Takeshi Noda
CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama, Japan

Yoko Fujita-Fujiharu & Takeshi Noda
RIKEN Spring-8 Center, Kouto, Sayo-cho, Sayo-gun, Hyogo, Japan

Masaki Yamamoto, Hideki Shigematsu & So Iwata
Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden

David Drew

Authors

Jinta Asami

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Kanako Terakado Kimura

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Yoko Fujita-Fujiharu

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Hanako Ishida

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Zhikuan Zhang

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Yayoi Nomura

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Kehong Liu

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Tomoko Uemura

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Yumi Sato

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Masatsugu Ono

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Masaki Yamamoto

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Takeshi Noda

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Hideki Shigematsu

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David Drew

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So Iwata

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Toshiyuki Shimizu

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Norimichi Nomura

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Umeharu Ohto

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Corresponding authors

Correspondence to Norimichi Nomura or Umeharu Ohto.

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Asami, J., Kimura, K.T., Fujita-Fujiharu, Y. et al. Structure of bile acid transporter NTCP crucial for hepatitis B virus entry. Nature (2022). https://ift.tt/o6TRdVW

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Received: 30 August 2021
Accepted: 09 May 2022
Published: 17 May 2022
DOI: https://ift.tt/o6TRdVW

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Structure of bile acid transporter NTCP crucial for hepatitis B virus entry - Nature.com

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