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Abstract
Superantigens are toxins produced by Staphylococcus aureus, called staphylococcal enterotoxins (abbreviated SEA to SEU). They can cross-link the T cell receptor (TCR) and major histocompatibility complex class II, triggering a massive T cell activation and hence disease. Due to high stability and toxicity, superantigens are potential agents of bioterrorism. Hence, antagonists may not only be useful in the treatment of disease but also serve as countermeasures to biological warfare. Of particular interest are inhibitors against SEA and SEB. SEA is the main cause of food poisoning, while SEB is a common toxin manufactured as a biological weapon. Here, we present the crystal structures of SEA in complex with TCR and SEE in complex with the same TCR, complemented with computational alanine-scanning mutagenesis of SEA, SEB, SEC3, SEE, and SEH. We have identified two common areas that contribute to the general TCR binding for these superantigens. This paves the way for design of single antagonists directed towards multiple toxins.
Highlights
Superantigens (SAgs) are immune stimulatory toxins secreted by bacteria, such as Staphylococcus aureus, which are capable of evoking an immune response of large proportions[1]
Class II binding site not involved in T cell receptor (TCR) binding, was crystallized in complex with the human TCR variable domains TRAV22 and TRBV7-9 in space group P21212, and the structure was determined to 3.1 Å resolution (Table 1)
TRAV22 and TRBV7-9 were isolated from two TCRs specific for HLA-A2 in complex either with a telomerase peptide or a survivin peptide, respectively
Summary
Superantigens (SAgs) are immune stimulatory toxins secreted by bacteria, such as Staphylococcus aureus, which are capable of evoking an immune response of large proportions[1]. By combining these structures with the previously published SEB-TCR structure[14], SEC3-TCR15 and SEH-TCR structure[16], with in silico alanine scanning mutagenesis, we can make predictions about which residues are most important for protein complex formation This is the first comprehensive analysis to tie all published data available, concerning TCR recognition by superantigens, together with computational analyses to identify a core set of conserved interactions present in SAg-TCR. This allows us to identify common structural elements likely to be useful for the design of broad spectrum SAg antagonists to abrogate SAg-TCR complex formation and neutralize the mitogenic activity of superantigens
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