While these studies clearly demonstrated that S598 Q600Y is heteroclitic, they did not provide a mechanism for the immune enhancement. To address this, we determined the crystal structures of the H-2K b /S598 (PDBid 2ZSV, Protein Data Bank Japan (http://www.pdbj.org/)) and H-2K b /S598 Q600Y (PDBid 2ZSW) complexes to 1.8 Å and 2.8 Å resolution respectively. The structure of H-2K b /S598 consists of two heterodimers in the asymmetric unit (r.m.s.d. of 0.18 Å for Ca atoms), with the S598 peptide clearly bound in the antigen binding cleft of the heavy chains (HC, Figure S3A ). The two peptide copies display a virtually identical configuration with root mean square deviation (rmsd) values of only 0.09 Å for all peptide atoms (0.05 Å for Ca atoms). The mode of S598 and S598 Q600Y binding within the Agbinding cleft is unambiguous, with the exception of Arg-1, whose side chain is partially disordered (Figure 5A,D; Figure S3C ). The S598 peptide adopts an extended conformation, with the side chains of Arg-1, Ile-4 and Asn-7 extending prominently out of the cleft ( Figure 5C ). Ala-6 is also largely solvent exposed with its side chain pointing towards the a2 helix, while the side chains of Cys (Aba)-2, Gln-3, Phe-5 and Ile-8 are buried within the cleft. While the cysteine analogue's side chain is not involved in any hydrophilic interactions, there are a number of suitably positioned hydrogen bonding partners (Glu-24, Tyr-45 and Asn-70), with which the original thiol side chain could potentially interact ( Figure S3B ; Table S2 ).