Structure of the bile acid transporter and HBV receptor NTCP

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, Hideki Shigematsu, David Drew, So Iwata, Toshiyuki Shimizu, Norimichi Nomura () and Umeharu Ohto ()
Additional contact information
Jinta Asami: The University of Tokyo
Kanako Terakado Kimura: Kyoto University
Yoko Fujita-Fujiharu: Kyoto University
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
Hideki Shigematsu: RIKEN SPring-8 Center
David Drew: Stockholm University
So Iwata: Kyoto University
Toshiyuki Shimizu: The University of Tokyo
Norimichi Nomura: Kyoto University
Umeharu Ohto: The University of Tokyo

Nature, 2022, vol. 606, issue 7916, 1021-1026

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-04845-4

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