A functional hot spot for antigen recognition in a superagonist TCR/MHC complex

A longstanding question in T cell receptor signaling is how structurally si milar ligands, with similar affinities, can have substantially different bi ological activity. The crystal structure of the 2C TCR complex of H-2K(b) w ith superagonist peptide SIYR at 2.8 Angstrom elucidates a structural basis for TCR discrimination of altered peptide ligands. The difference in antig en potency is modulated by two cavities in the TCR combining site, formed m ainly by CDRs 3 alpha, 3 beta, and 1 beta, that complement centrally locate d peptide residues. This "functional hot spot" allows the TCR to finely dis criminate amongst energetically similar interactions within different ligan ds for those in which the peptide appropriately stabilizes the TCR/pMHC com plex and provides a new structural perspective for understanding differenti al signaling resulting from T cell cross-reactivity.