Structural basis of the hepatitis B virus X protein in complex with DDB1

• 成果类型: Article
• 署名作者: Tanaka, Hiroki; Dias, Joao Diogo; Jay, Basile; Kita, Shunsuke; Sasaki, Mina; Takeda, Hiroyuki; Kishimoto, Naoki; Sasaki, Shunsuke; Misumi, Shogo; Mizokami, Masashi; Neuveut, Christine; Sumikama, Takashi; Shibata, Mikihiro; Maenaka, Katsumi; Machida, Shinichi
• 署名单位: Universite de Montpellier; Centre National de la Recherche Scientifique (CNRS); Hokkaido University; Ehime University; Kumamoto University; Japan Institute for Health Security (JIHS); National Center for Global Health & Medicine - Japan; Kanazawa University; Kanazawa University; Hokkaido University; Hokkaido University; Hokkaido University; Kumamoto University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8465
• DOI: 10.1073/pnas.2421325122
• 发表日期: 2025-06-17
• 关键词: inhibits hbv replication; smc5/6 complex; homologous recombination; dna-repair; degradation; cccdna; gene; ORGANIZATION; cycle

摘要

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 simultaneouslywith 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.