Structural basis of Deerpox virus-mediated inhibition of apoptosis

Acta Crystallogr D Biol Crystallogr. 2015 Aug;71(Pt 8):1593-603. doi: 10.1107/S1399004715009402. Epub 2015 Jul 28.


Apoptosis is a key innate defence mechanism to eliminate virally infected cells. To counteract premature host-cell apoptosis, poxviruses have evolved numerous molecular strategies, including the use of Bcl-2 proteins, to ensure their own survival. Here, it is reported that the Deerpox virus inhibitor of apoptosis, DPV022, only engages a highly restricted set of death-inducing Bcl-2 proteins, including Bim, Bax and Bak, with modest affinities. Structural analysis reveals that DPV022 adopts a Bcl-2 fold with a dimeric domain-swapped topology and binds pro-death Bcl-2 proteins via two conserved ligand-binding grooves found on opposite sides of the dimer. Structures of DPV022 bound to Bim, Bak and Bax BH3 domains reveal that a partial obstruction of the binding groove is likely to be responsible for the modest affinities of DPV022 for BH3 domains. These findings reveal that domain-swapped dimeric Bcl-2 folds are not unusual and may be found more widely in viruses. Furthermore, the modest affinities of DPV022 for pro-death Bcl-2 proteins suggest that two distinct classes of anti-apoptotic viral Bcl-2 proteins exist: those that are monomeric and tightly bind a range of death-inducing Bcl-2 proteins, and others such as DPV022 that are dimeric and only bind a very limited number of death-inducing Bcl-2 proteins with modest affinities.

Keywords: Bcl-2; X-ray crystallography; apoptosis; poxvirus.

MeSH terms

  • Amino Acid Sequence
  • Apoptosis*
  • Crystallography, X-Ray
  • Host-Pathogen Interactions
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Poxviridae / chemistry*
  • Poxviridae / metabolism
  • Poxviridae Infections / metabolism
  • Poxviridae Infections / virology*
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-bcl-2 / chemistry*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Sequence Alignment
  • Viral Proteins / chemistry*
  • Viral Proteins / metabolism


  • Proto-Oncogene Proteins c-bcl-2
  • Viral Proteins