Structural basis of the hepatitis B virus X protein in complex with DDB1
A cure for chronic hepatitis B requires eliminating or permanently silencing covalently closed circular DNA (cccDNA). A pivotal target of this approach is the hepatitis B virus (HBV) X protein (HBx), which is a key factor that promotes transcription from cccDNA. However, the HBx structure remains unsolved. Here, we present the cryoelectron microscopy structure of HBx in complex with DDB1, which is an essential complex for cccDNA transcription. In this structure, hydrophobic interactions within HBx were identified, and mutational analysis highlighted their importance in the HBV life cycle. Our biochemical analysis revealed that the HBx-DDB1 complex directly interacts simultaneously with NSE3, which is a component of the SMC5/6 complex, and Spindlin1. Additionally, HBx-DDB1 complex dynamics were explored via high-speed atomic force microscopy. These findings provide comprehensive insights into the structure and function of HBx in HBV replication.
Authors
- Basile Jay (ORCID: https://orcid.org/0000-0001-8573-8722)
- Takashi Sumikama (ORCID: https://orcid.org/0000-0003-3696-5720)
- Katsumi Maenaka (ORCID: https://orcid.org/0000-0002-5459-521X)
- Shunsuke Sasaki (ORCID: https://orcid.org/0000-0001-8358-1629)
- Mikihiro Shibata (ORCID: https://orcid.org/0000-0001-5041-3979)
- Naoki Kishimoto (ORCID: https://orcid.org/0000-0002-9401-8118)
- Hiroki Tanaka (ORCID: https://orcid.org/0000-0002-7404-3527)
- Hiroyuki Takeda (ORCID: https://orcid.org/0000-0003-1677-8127)
- Shogo Misumi (ORCID: https://orcid.org/0000-0002-9465-4720)
- Shunsuke Kita (ORCID: https://orcid.org/0000-0003-3969-302X)
- Joao Diogo Dias (ORCID: https://orcid.org/0009-0007-8979-6779)
- Christine Neuveut (ORCID: https://orcid.org/0000-0001-6520-271X)
- Shinichi Machida (ORCID: https://orcid.org/0009-0002-8891-4888)
- Mina Sasaki (ORCID: https://orcid.org/0009-0006-6743-8789)
- Masashi Mizokami (ORCID: https://orcid.org/0000-0001-5269-4006)
Institutions
- Kanazawa University (JP)
- Hokkaido University of Science (JP)
- Centre National de la Recherche Scientifique (FR)
- Kumamoto Health Science University (JP)
- Université de Montpellier (FR)
- Hokkaido University (JP)
- National Center for Global Health and Medicine (JP)
- Life Science Institute (JP)
- Institut de Génétique Moléculaire de Montpellier (FR)
- Institut de Recherche Vaccinale (FR)
- Center for Global Health (US)
- BioSurfaces (United States) (US)
- Ehime University (JP)
- Kumamoto University (JP)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-06-13
- DOI
- https://doi.org/10.1073/pnas.2421325122
- Citations
- 5
- Primary Topic
- Hepatitis B Virus Studies
- Type
- article
- Field-Weighted Citation Impact
- 6.77
Funders
- Japan Agency for Medical Research and Development
- National Center for Global Health and Medicine
- Japan Society for the Promotion of Science