With respect to the HC, the a-1 and a-2 domains of the two structures superimpose well with an rmsd of 0.37 Å for Ca atoms (residues 1-176). Nevertheless, significant deviations (.0.5 Å ) are observed between the two structures at a number of positions in the region of the antigen binding cleft. In particular, changes in the conformation of Ser-99, Gln-114, and Gly-151-Glu-154 are associated with the bound peptides. Changes in the side chain conformations of Ser-99 and Gln-114 in the Q600Y complex structure are consistent with the loss of hydrogen bonding interactions with position 3. In the wild type peptide structure, Glu-152 forms a salt bridge with Arg-155, the guanadinium group of which also forms a hydrogen bond with the main chain carbonyl group of the peptide's Ile-4. While these interactions are maintained in the Q600Y complex, the side chain of Glu-152 displays a conformational shift consistent with the formation of a hydrogen bond with the peptide's Tyr-3 ( Figure 6 ). Interestingly the region of the a-2 helix around Glu-152 (Gly-151 -Glu-154) also displays significant main chain and side chain deviations between the two structures (rmsd of 0.77 Å for Ca atoms; Figure 6 ). Thus, consistent with the functional analyses, the structure of the heteroclitic variant of the S598 epitope displays relatively small changes in conformation yet the combination of these subtle changes in the TcR accessible residues and the structural landscape of the MHCp in addition to the enhanced stability of the complex lead to more efficacious CTL responses.