Structural basis of hepatitis B virus receptor binding.

Area of Science:

• Virology
• Structural Biology
• Hepatology

Background:

• Hepatitis B virus (HBV) infects over 290 million people globally, leading to hepatocellular carcinoma.
• HBV entry into hepatocytes is mediated by the myristoylated preS1 domain of the large surface protein binding to sodium-taurocholate cotransporting polypeptide (NTCP).

Purpose of the Study:

• To determine the cryogenic-electron microscopy (cryo-EM) structure of the myristoylated preS1 peptide bound to human NTCP.
• To elucidate the molecular mechanism of HBV-host receptor attachment and viral entry.

Main Methods:

• Cryogenic-electron microscopy (cryo-EM) was used to visualize the complex of the myristoylated preS1 peptide (residues 2-48) and human NTCP.
• Structural analysis focused on the binding interface and conformational changes.

Main Results:

• The structure reveals an unexpected folding of the preS1 peptide within the NTCP transporter.
• The N-terminal half of the peptide embeds into the outward-facing tunnel of NTCP, while the C-terminal half interacts with the extracellular surface.
• This interaction demonstrates an induced-fit mechanism facilitating high-affinity binding.

Conclusions:

• The study reveals the structural basis of HBV attachment to hepatocytes via the NTCP receptor.
• The findings provide a detailed understanding of the induced-fit mechanism governing HBV entry.
• This structural blueprint can guide the rational design of novel anti-HBV therapeutics targeting viral entry.