Structure of the bile acid transporter and HBV receptor NTCP

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 annually(1,2). For HBV infection to be established, a molecular interaction is required between the large glycoproteins ofthe 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 hepatocytes(3). 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 acrossthe 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 ofthe 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.

Automated summary

Chronic infection with hepatitis B virus (HBV) requires interaction between the large glycoproteins of the virus envelope (LHBs) and the host entry receptor sodium taurocholate co-transporting polypeptide (NTCP). This study reveals the structures of NTCP and identifies a possible transport route for substrate. Furthermore, the study suggests a binding mode between LHBs and NTCP, which explains naturally occurring HBV-insusceptible mutations in NTCP.