Crystal structures of the sheeppoxvirus encoded inhibitor of apoptosis SPPV14 bound to Hrk and Bax BH3 peptides

Programmed death of infected cells is used by multicellular organisms to counter viral infections. Sheeppoxvirus encodes for SPPV14, a potent inhibitor of Bcl-2 mediated apoptosis. We reveal the structural basis of apoptosis inhibition by determining crystal structures of SPPV14 bound to BH3 motifs of proapoptotic Bax and Hrk. The structures reveal that SPPV14 engages BH3 peptides using the canonical ligand binding groove. Unexpectedly, Arg84 from SPPV14 forms an ionic interaction with the conserved Asp in the BH3 motif in a manner that replaces the canonical ionic interaction seen in almost all host Bcl-2:BH3 motif complexes. These results reveal the flexibility of virus encoded Bcl-2 proteins to mimic key interactions from endogenous host signalling pathways to retain BH3-binding and pro-survival functionality.