Food for Health


Date of this Version


Document Type



J Mol Biol. 2011 December 2; 414(3): 385–400. doi:10.1016/j.jmb.2011.10.006.




αβ T cell receptors recognize multiple antigenic peptides bound and presented by major histocompatibility complex molecules. TCR cross-reactivity has been attributed in part to flexibility of the complementarity-determining region loops, yet there have been limited direct studies of loop dynamics to determine the extent of its role. Here we studied the flexibility of the binding loops of the αβ TCR A6 utilizing crystallographic, spectroscopic, and computational methods. A significant role for flexibility in binding and cross-reactivity was indicated only for the CDR3α and CDR3β hypervariable loops. Examination of the energy landscapes of these two loops indicated that CDR3β possesses a broad, smooth landscape, leading to the rapid sampling in the free TCR of a range of conformations compatible with different ligands. The landscape for CDR3α is more rugged, resulting in limited conformational sampling that leads to specificity towards a reduced set of peptides as well as MHC. In addition to informing on the mechanisms of cross-reactivity and specificity, the energy landscapes of the two loops indicate a complex mechanism for TCR binding, incorporating elements of both conformational selection and induced-fit in a manner that blends features of popular models for TCR recognition.