Cutting edge: A single, essential hydrogen bond controls the stability of peptide-MHC class II complexes

The binding of peptides to MHC class II molecules is mediated in part by a conserved array of intermolecular hydrogen bonds. We have evaluated the con sequences of disrupting the hydrogen bond between beta-His-81 of the class II molecule and bound peptide. These studies revealed that peptide dissocia tion rates were accelerated by factors ranging to 200-fold. The sensitivity of a peptide to loss of the hydrogen bond is inversely correlated with the inherent kinetic stability of the peptide-MHC complex. The same relationsh ip has been observed between inherent kinetic stability and the susceptibil ity to DM. Given that the rate enhancement observed for MHC class II I-Ad p rotein mutated at position 81 in the beta-chain is comparable with DM-catal yzed rates for other class II molecules, we suggest that DM could function by stabilizing a peptide-MHC intermediate in which one or more hydrogen bon ds between the peptide and MHC, such as that contributed by the beta-His-81 hydrogen bond, are disrupted.