MOLECULAR MODELING OF A T-CELL RECEPTOR-BOUND TO A MAJOR HISTOCOMPATIBILITY COMPLEX MOLECULE - IMPLICATIONS FOR T-CELL RECOGNITION

The main functions of the T-cell receptor (TCR) involve its specific i nteraction with short and linear antigenic peptides bound to the major histocompatibility complex (MHC) molecules. In the absence of a 3D st ructure for TCR and for the TCR/peptide/MHC complex, several attempts to characterize the structural components of the TCR/peptide/MHC inter action have been made. However, this subject is still troublesome. In this paper a computer-based 3D model for a TCR/peptide/MHC complex (5C .C7/moth cytochrome c [MCC] peptide 93-103/I-E(k)) was obtained. The c omplex surface shows a high complementarity between the 5C.C7 structur e and the peptide/I-E(k) molecule. The mapping of residues involved in the TCR/peptide/MHC interaction shows close agreement with mutational experiments (Jorgensen JL, Reay PA, Ehrich EW, Davis MM, 1992b, Annu Rev Immunol 10:835-873). Moreover, the results are consistent with a r ecent variability analysis of TCR sequences using three variability in dexes (Almagro JC, Zenteno-Cuevas R, Vargas-Madrazo E, Lara-Ochoa F, 1 995b, Int J Pept Protein Res 45:180-186). Accordingly, the 3D model of the 5C.C7/MCC peptide 93-103/I-E(k) complex provides a framework to g enerate testable hypotheses about TCR recognition. Thus, starting from this model, the role played by each loop that forms the peptide/MHC b inding site of the TCR is discussed.