Role of 2C T cell receptor residues in the binding of self- and allo-majorhistocompatibility complexes

T cell done 2C recognizes the alloantigen Ld and the positive selecting maj or histocompatibility complex (MHC), K-b. To explore the molecular basis of T cell antigen receptor (TCR) binding to different peptide/MHC (pMHC) comp lexes, we performed alanine scanning mutagenesis of the 2C TCR. The TCR ene rgy maps for QL9/L-d and SIYR/K-b were remarkably similar, in that 16 of 41 V alpha and V beta alanine mutants showed reduced binding to both ligands, Several TCR residues varied in the magnitude of energy contributed to bind ing the two ligands, indicating that there are also unique interactions. Re sidues in complementarity determining region 3 alpha showed the most notabl e differences in binding energetics among the ligands QL9/L-d, SIYR/K-b, an d the clonotypic antibody 1B2. Various lines of evidence suggest that these differences relate to the mobility of this loop and point to the key role of conformational dynamics in pMHC recognition.