Two different T cell receptors use different thermodynamic strategies to recognize the same peptide/MHC ligand.

A6 and B7 are two alphabeta T cell receptors (TCRs) that recognize the Tax peptide presented by the class I major histocompatibility molecule HLA-A2 (Tax/HLA-A2). Despite the fact that the two TCRs have different CDR loops and use different amino acid residues to contact their ligand, both receptors bind ligand with similar diagonal orientations. Here we show that they also bind with very similar binding affinities and kinetics (the DeltaDeltaG degrees for binding is approximately 0.3kcal/mol at 25 degrees C). The two receptors respond similarly to alterations in the MHC molecule, yet differ dramatically in their responses to ionic strength and temperature. The different responses to temperature indicate markedly different binding thermodynamics, which are not predictable from the surface area buried in the interfaces. A6 and B7 thus represent two TCRs that are both compatible with Tax/HLA-A2, although compatibility has been achieved through the use of different thermodynamic strategies. Finally, neither A6 nor B7 are predicted to undergo large conformational adaptations upon binding, distinguishing them from a number of other TCRs whose structure, thermodynamics, and kinetics have been characterized.