Structural and biochemical analysis of Bcl-2 interaction with the hepatitis B virus protein HBx

Proc Natl Acad Sci U S A. 2016 Feb 23;113(8):2074-9. doi: 10.1073/pnas.1525616113. Epub 2016 Feb 8.


HBx is a hepatitis B virus protein that is required for viral infectivity and replication. Anti-apoptotic Bcl-2 family members are thought to be among the important host targets of HBx. However, the structure and function of HBx are poorly understood and the molecular mechanism of HBx-induced carcinogenesis remains unknown. In this study, we report biochemical and structural characterization of HBx. The recombinant HBx protein contains metal ions, in particular iron and zinc. A BH3-like motif in HBx (residues 110-135) binds Bcl-2 with a dissociation constant of ∼193 μM, which is drastically lower than that for a canonical BH3 motif from Bim or Bad. Structural analysis reveals that, similar to other BH3 motifs, the BH3-like motif of HBx adopts an amphipathic α-helix and binds the conserved BH3-binding groove on Bcl-2. Unlike the helical Bim or Bad BH3 motif, the C-terminal portion of the bound HBx BH3-like motif has an extended conformation and makes considerably fewer interactions with Bcl-2. These observations suggest that HBx may modulate Bcl-2 function in a way that is different from that of the classical BH3-only proteins.

Keywords: Bcl-2; apoptosis; crystal structure; hepatitis B virus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Crystallography, X-Ray
  • Hepatitis B virus / chemistry*
  • Hepatitis B virus / genetics
  • Hepatitis B virus / metabolism
  • Humans
  • Protein Binding
  • Proto-Oncogene Proteins c-bcl-2 / chemistry*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Trans-Activators / chemistry*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Viral Regulatory and Accessory Proteins


  • BCL2 protein, human
  • Proto-Oncogene Proteins c-bcl-2
  • Trans-Activators
  • Viral Regulatory and Accessory Proteins
  • hepatitis B virus X protein

Associated data

  • PDB/5FCG