Identification of a common docking topology with substantial variation among different TCR-peptide-MHC complexes

Whether T-cell receptors (TCRs) recognize antigenic peptides bound to major histocompatability complex (MHC) molecules through common or distinct docking modes is currently uncertain. We report the crystal structure of a complex between the murine N15 TCR [1-4] and its peptide-MHC ligand, an octapeptide fragment representing amino acids 52-59 of the vesicular stomatitis virus nuclear capsid protein (VSV8) bound to the murine H-2K(b) class I MHC molecule, Comparison of the structure of the N15 TCR-VSV8-H-2K(b) complex with the murine 2C TCR-dEV8-H-2K(b) [5] and the human A6 TCR-Tax-HLA-A2 [6] complexes revealed a common docking mode, regardless of TCR specificity or species origin, in which the TCR variable Va domain overlies the MHC alpha 2 helix and the V beta domain overlies the MHC alpha 1 helix, As a consequence, the complementary determining regions CDR1 and CDR3 of the TCR V alpha and V beta domains make the major contacts with the peptide, while the CDR2 loops interact primarily with the MHC, Nonetheless, in terms of the details of the relative orientation and disposition of binding, there is substantial variation in TCR parameters, which we term twist, tilt and shift, and which define the variation of the V module of the TCR relative to the MHC antigen-binding groove.