Many viruses encode proteins to control the apoptotic machinery of host cells. Among these viruses, the Pox viridae family has been shown to encode proteins that adopt a Bcl-2-like fold, and are able to hijack apoptosis signaling in an infected host cell after viral invasion. The protein DPV022 from the Deerpox virus and the protein SPPV014 from the sheeppox virus are susceptible to adopt a Bcl-2 fold to stem the host apoptosis. But currently, only few is known about these two proteins.

Previously, the binding partner for SPPV14 has been identified by some of our collaborators. We are currently attempting to identify pro-apoptotic interaction partners of DPV022, determine the structure of these two proteins and in particular their complexes with pro-apoptotic proteins by co-crystallization. Ultimately this could lead to a better understanding of the molecular mechanism of inhibition of apoptosis by poxviruses but also how works the Bcl-2 protein family.

In the process of ligand determination that we are investigating for DPV022, our initial results indicate that the BH3-only protein Bim is a high-affinity ligand. Moreover, we have been able to obtained initial crystals of DPV022 on its own and in complex Bim. For SPPV014, we are able to co-express it with one of its best ligand, Bim. Also, crystal trials have been successful and lead to co-crystals that we are now trying to improve. The determination of these structures will allow for specific site-directed mutagenesis focusing on key binding residues to gain further insight into DPV022 and SPPV014 mediated inhibition of apoptosis, and improve our understanding of mammalian cell death regulation.