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A Protocol for Analyzing Hepatitis C Virus Replication
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Promiscuous Metal Site in Hepatitis B Virus X Protein Binds an Fe-S Cluster
Jiahua Chen1, Michelle Langton1, Patrick Cao1
1Department of Biochemistry, Brandeis University, Waltham, Massachusetts 02453, United States.
Biorxiv : the Preprint Server for Biology
|February 6, 2026
Summary
The Hepatitis B virus (HBV) regulatory protein HBx uses specific cysteine residues to bind an iron-sulfur (Fe-S) cluster, crucial for viral replication. This discovery reveals a potential new target for antiviral therapies against HBV.
Area of Science:
- Biochemistry
- Virology
- Molecular Biology
Background:
- The Hepatitis B virus (HBV) regulatory protein HBx is vital for viral replication and disease.
- Its cofactor specificity and metal-binding environment are not well understood.
- HBx's intrinsic disorder and mutation tolerance complicate its characterization.
Purpose of the Study:
- To identify the specific metal-coordinating ligands within the HBx protein.
- To elucidate the role of metal binding in HBx function and HBV pathogenesis.
- To explore potential therapeutic vulnerabilities associated with HBx metal binding.
Main Methods:
- Integration of chemoproteomics and HYSCORE spectroscopy to map metal-binding sites.
- Mutational analysis to confirm the role of identified cysteine residues.
- Assessment of HBx interaction with host Fe-S cluster machinery.
Main Results:
- Cysteine residues C61, C69, C143, and C148 were identified as primary ligands for an Fe-S cluster.
- Cysteine C137 acts as a conditional ligand for the Fe-S cluster.
- These residues also coordinate with zinc and are linked to HBx transactivation and disease-relevant variants.
- HBx interacts with host cytosolic Fe-S machinery and is sensitive to Fe-S-targeting agents.
Conclusions:
- HBx functions as an Fe-S cluster-associated protein.
- The identified metal-binding site represents a potential druggable target for inhibiting HBV replication.
- Understanding HBx metal coordination provides new insights into HBV pathogenesis.
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