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

Abstract

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-2Kb class I MHC molecule. Comparison of the structure of the N15 TCR-VSV8-H-2Kb complex with the murine 2C TCR-dEV8-H-2Kb [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 Valpha domain overlies the MHC alpha2 helix and the Vbeta domain overlies the MHC alpha1 helix. As a consequence, the complementary determining regions CDR1 and CDR3 of the TCR Valpha and Vbeta 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.

Molecular Recognition of Human CD1b Antigen Complexes: Evidence for a Common Pattern of Interaction with αβ TCRs

“…Although not yet demonstrated by direct experimental evidence, this orientation appears reasonable based on the modeling and also on the fact that all TCR/MHC complexes analyzed by x-ray crystallography thus far show this orientation (17)(18)(19)(20)(21)(22). In docking the two proteins during the generation of that model, it was noted that the increased elevation of the peaks of the CD1b ␣1 and ␣2 helices and the smaller distance between the two ␣ helices in comparison with MHC class I molecules prevented placement of the TCR in the same orientation as observed for TCR/H-2K b interactions.…”

“…TCR interactions with MHC class I and class II molecules have been extensively analyzed (1,2), and the crystal structures of trimolecular complexes formed among ␣␤ TCRs, MHC class I/peptide complexes (17)(18)(19)(20)(21), and MHC class II/peptide complexes (22) have recently been solved. These structures reveal that the TCR recognizes a surface on the MHC class I and class II molecules formed by the two membrane distal domains of each molecule (␣1 and ␣2 for MHC class I and ␣1 and ␤1 for MHC class II).…”

Molecular Basis of Peptide Recognition by the TCR: Affinity Differences Calculated Using Large Scale Computing

“…These residues lie around the breaks in the two helical regions, which form the "high points" on the binding surface. The "high points" impose a critical constraint which causes the TCR to dock with a pMHC ligand in "diagonal mode" (29). E58 is at the "high point" and from P57 to P50 the chain runs away from the TCR-binding surface.…”

Immunobiological Analysis of TCR Single-Chain Transgenic Mice Reveals New Possibilities for Interaction between CDR3α and an Antigenic Peptide Bound to MHC Class I

“…Next we used a series of H-2K b mutants to map the TCR binding surface on the MHC, work that allowed us to first propose the diagonal orientation of TCR over pMHC (20). Structural information regarding the interaction of TCRs with VSV8/H-2K b is limited to a single low-resolution structure that is nonetheless sufficient to confirm the overall diagonal orientation observed in the TCR/pMHC structures that have been reported in other systems (21).…”