TCR binding to peptide-MHC stabilizes a flexible recognition interface

The binding of TCRs to their peptide-MHC ligands is characterized by a low affinity, slow kinetics, and a high degree of cross-reactivity, Here, we re port the results of a kinetic and thermodynamic analysis of two TCRs bindin g to their peptide-MHC ligands, which reveal two striking features. First, significant activation energy barriers must be overcome during both associa tion and dissociation, suggesting that conformational adjustments are requi red. Second, the low affinity of binding is a consequence of highly unfavor able entropic effects, indicative of a substantial reduction in disorder up on binding. This is evidence that the TCR and/or peptide-MHC have flexible binding surfaces that are stabilized upon binding. Such conformational flex ibility, which may also be a feature of primary antibodies, is likely to co ntribute to cross-reactivity in antigen recognition.