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Updated: Jun 15, 2025

Identifying Inhibitors of the HBx-DDB1 Interaction Using a Split Luciferase Assay System
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Structural basis of the hepatitis B virus X protein in complex with DDB1

Hiroki Tanaka1, Joao Diogo Dias2, Basile Jay2

  • 1Department of Structural Virology, National Institute of Global Health and Medicine, Japan Institute for Health Security, Shinjuku-ku, Tokyo 162-8655, Japan.

Proceedings of the National Academy of Sciences of the United States of America
|June 13, 2025
PubMed

Insights

Researchers solved the structure of hepatitis B virus X protein (HBx) complexed with DDB1, revealing key interactions essential for viral replication and offering new targets for chronic hepatitis B cures.

Area of Science:

  • Virology
  • Structural Biology
  • Molecular Biology

Background:

  • Chronic hepatitis B treatment requires targeting covalently closed circular DNA (cccDNA).
  • The hepatitis B virus X protein (HBx) is crucial for cccDNA transcription but its structure is unknown.

Purpose of the Study:

  • To determine the structure of the HBx-DDB1 complex.
  • To elucidate the role of HBx structure and interactions in HBV replication.

Main Methods:

  • Cryoelectron microscopy to solve the HBx-DDB1 complex structure.
  • Mutational analysis to assess the importance of identified hydrophobic interactions.
  • Biochemical assays to map interactions with NSE3 and Spindlin1.
  • High-speed atomic force microscopy to study complex dynamics.

Main Results:

  • The cryoelectron microscopy structure of the HBx-DDB1 complex was determined.
  • Key hydrophobic interactions within HBx were identified and shown to be important for the HBV life cycle.
  • The HBx-DDB1 complex was found to interact with NSE3 (SMC5/6 complex component) and Spindlin1.
  • Complex dynamics were visualized using high-speed atomic force microscopy.

Conclusions:

  • Structural and biochemical insights into the HBx-DDB1 complex provide a deeper understanding of its role in HBV replication.
  • The findings offer potential new strategies for developing therapies against chronic hepatitis B by targeting HBx.

Keywords:
HBxcryo-EM structurehepatitis B virushigh-speed AFM

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