ArticleJournal of virology2019
Hepatitis B Virus X Protein Function Requires Zinc Binding.
Article in Journal of virology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed.
- Mössbauer spectroscopy in drug discovery: revealing Fe- and Fe-S cluster dependent targets.Expert opinion on drug discovery · 2026Review
- Structural and functional insights into HBx-Smc6 targeting for HBV inhibition.Cell research · 2026Article
- HBV HBx protein masks epigenetic reader Spindlin1 via an inter-molecular zinc finger to subvert transcriptional control.Nature communications · 2026Article
- Trace Elements and Viral Infectious Diseases: Dual Roles in Pathogenesis and Immunity.Infectious disease reports · 2026Review
- Novel C-terminal HBx truncation (G135) in genotype D1 HBV: predicted effects on oncogenic signaling.Infectious agents and cancer · 2026Article
- Promiscuous Metal Site in Hepatitis B Virus X Protein Binds an Fe-S Cluster.bioRxiv : the preprint server for biology · 2026Article
- Sequential backbone chemical shift assignments of a cancer-associated isoform of the HBx protein from human hepatitis B virus.Biomolecular NMR assignments · 2025Article
- Structural basis of the hepatitis B virus X protein in complex with DDB1.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- The Intrinsically Disordered Region of HBx and Virus-Host Interactions: Uncovering New Therapeutic Approaches for HBV and Cancer.International journal of molecular sciences · 2025Review
- Mass Spectrometry-Based Protein Footprinting for Protein Structure Characterization.Accounts of chemical research · 2025Article
- Review
- Iron‑sulfur clusters in viral proteins: Exploring their elusive nature, roles and new avenues for targeting infections.Biochimica et biophysica acta. Molecular cell research · 2024Review
- Article
- The Cryptic Nature of Fe-S Clusters: A Case Study of the Hepatitis B HBx Oncoprotein.Inorganics · 2023Article
- The Fe and Zn cofactor dilemma.Biochimica et biophysica acta. Proteins and proteomics · 2023Review
- Molecular insights into Spindlin1-HBx interplay and its impact on HBV transcription from cccDNA minichromosome.Nature communications · 2023Article
- Relevance of HBx for Hepatitis B Virus-Associated Pathogenesis.International journal of molecular sciences · 2023Review
- Structural mechanism of CRL4-instructed STAT2 degradation via a novel cytomegaloviral DCAF receptor.The EMBO journal · 2023Article
- Antiviral activity of zinc against hepatitis viruses: current status and future prospects.Frontiers in microbiology · 2023Review
- Pregenomic RNA Launch Hepatitis B Virus Replication System Facilitates the Mechanistic Study of Antiviral Agents and Drug-Resistant Variants on Covalently Closed Circular DNA Synthesis.Journal of virology · 2022Article
Corrections and comments
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Authors and funding
15 authors.
Funding
Abstract
The host structural maintenance of chromosomes 5/6 complex (Smc5/6) suppresses hepatitis B virus (HBV) transcription. HBV counters this restriction by expressing the X protein (HBx), which redirects the cellular DNA damage-binding protein 1 (DDB1)-containing E3 ubiquitin ligase to target Smc5/6 for degradation. However, the details of how HBx modulates the interaction between DDB1 and Smc5/6 remain to be determined. In this study, we performed biophysical analyses of recombinant HBx and functional analysis of HBx mutants in HBV-infected primary human hepatocytes (PHH) to identify key regions and residues that are required for HBx function. We determined that recombinant HBx is soluble and exhibits stoichiometric zinc binding when expressed in the presence of DDB1. Mass spectrometry-based hydrogen-deuterium exchange and cysteine-specific chemical footprinting of the HBx:DDB1 complex identified several HBx cysteine residues (located between amino acids 61 and 137) that are likely involved in zinc binding. These cysteine residues did not form disulfide bonds in HBx expressed in human cells. In line with the biophysical data, functional analysis demonstrated that HBx amino acids 45 to 140 are required for Smc6 degradation and HBV transcription in PHH. Furthermore, site-directed mutagenesis determined that C61, C69, C137, and H139 are necessary for HBx function, although they are likely not essential for DDB1 binding. This CCCH motif is highly conserved in HBV as well as in the X proteins from various mammalian hepadnaviruses. Collectively, our data indicate that the essential HBx cysteine and histidine residues form a zinc-binding motif that is required for HBx function.
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