Structure of the bile acid transporter and HBV receptor NTCP

Nature. 2022 Jun;606(7916):1021-1026. doi: 10.1038/s41586-022-04845-4. Epub 2022 May 17.


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.

MeSH terms

  • Animals
  • Apoproteins / chemistry
  • Apoproteins / genetics
  • Apoproteins / metabolism
  • Apoproteins / ultrastructure
  • Cattle
  • Cryoelectron Microscopy*
  • Hepatitis B virus* / metabolism
  • Hepatocytes / metabolism
  • Humans
  • Mutation
  • Organic Anion Transporters, Sodium-Dependent* / chemistry
  • Organic Anion Transporters, Sodium-Dependent* / genetics
  • Organic Anion Transporters, Sodium-Dependent* / metabolism
  • Organic Anion Transporters, Sodium-Dependent* / ultrastructure
  • Rats
  • Receptors, Virus* / chemistry
  • Receptors, Virus* / genetics
  • Receptors, Virus* / metabolism
  • Receptors, Virus* / ultrastructure
  • Sodium / metabolism
  • Symporters* / chemistry
  • Symporters* / genetics
  • Symporters* / metabolism
  • Symporters* / ultrastructure


  • Apoproteins
  • Organic Anion Transporters, Sodium-Dependent
  • Receptors, Virus
  • Symporters
  • sodium-bile acid cotransporter
  • Sodium