Crystal structure of a superantigen bound to the high-affinity, zinc-dependent site on MHC class II

MHC class II molecules possess two binding sites for bacterial superantigen s (SAGs): a low-affinity site on the cu chain and a high-affinity, zinc-dep endent site on the beta chain. only the former has been defined crystallogr aphically. We report the structure of streptococcal pyrogenic exotoxin C (S PE-C) complexed with HLA-DR2a (DRA*010l, DRB5*0101) bearing a self-peptide from myelin basic protein (MBP). SPE-C binds the beta chain through a zinc bridge that links the SAG and class II molecules. Surprisingly, SPE-C also makes extensive contacts with the MBP peptide, such that peptide accounts f or one third of the surface area of the MHC molecule buried in the complex, similar to TCR-peptide/MHC complexes. Thus, SPE-C may optimize T cell resp onses by mimicking the peptide dependence of conventional antigen presentat ion and recognition.