The model structures of four trimer complexes reveal the diversity in Sags binding.

In the first structure, SEC3 (similar to SEB) is bound to the conserved MHC class II α-chain and engages a Vβ8 domain [18],[19]. Note how the TcR makes no contact with the normal peptide/MHC surface as it would during normal peptide recognition. In the second structure TSST binds in the same location as SEC3 but in a different orientation. TSST is very specific for the human Vβ2 TcR [20],[21]. In the third structure, the streptococcal Sag SPEC is bound to the other side of MHC class II and ligates human Vβ2 TcR [8],[22] but in a quite different orientation to TSST. The fourth structure is of staphylococcal enterotoxin H (SEH) bound to the β-chain of MHC class II but ligating a TcR through its Vα27 domain—the only Sag known to engage a TcR α-chain [9]. In each of the structures the location of the CD28 binding identified by Arad et al. [16] is represented by red space filling spheres. Note its position well away from both TcR and MHC class II in a suitable position to engage a CD28 molecule in a tetrameric membrane complex in each of the four Sag orientations.