Smallpox, the first eradicated virus, was successfully eliminated thanks to the Vaccinia virus vaccination. Vaccines against Vaccinia have largely targeted the poxvirus protein A33 (a conserved protein within the chordopoxvirinae subfamily). It wasn't until very recently, however, that the structure and function of this protein was identified.
The A33 poxvirus protein structure was studied through many methods. However, in X-ray crystallography of the protein it was discovered that the structure revealed C-type lectin-like domains, occurring in dimers. This bore remarkable resemblance to the CTLD structure seen in the binding of NK cells (specifically, "long-loop," dimeric protein binding). In further investigations of gene expression and protein folding, scientists realized that, just as CTLD in NK cells, A33 facilitates interactions with both viral and host ligands, acting as a binding protein.
In order to test it's efficacy as a binding protein, mutations and truncated versions of the A33 pox protein were made and tested in vitro. It was found that the viruses with mutations or truncated A33 proteins were much less virulent than the WT. All experiments supported the hypothesis that the pox proteins were CTLDs, and all findings implicated A33 as a crucial binding ligand.
Though smallpox has been eradicated, the identification of the viral CTLD B-sheet binding structure helps us understand common mechanisms of viral invasion and replication. Furthermore, as we observed in tests of the truncated proteins, the binding proteins (which seem to have similar dimeric domains as our own cells) are important to viral virulence. Therefore, perhaps targeting the CTLDs/ binding proteins of not only poxviridae but also other viral families as well could lead the discovery of new forms of vaccines.