Mutations changing the kinetics of class II MHC peptide exchange

IE/DR MHC class II molecules have an extensive H-bonding network under the bound peptide. In IEk, two or chain acidic amino acids in the core of this network were mutated to amides. At low pH, the mutant molecule exchanged pe ptide much more rapidly than the wild-type. The crystal structure of the mu tant IEk revealed the loss of a single buried water molecule and a reorgani zation of the predicted H-bonding network. We suggest that these mutations enhance the transition of MHC class II to an open conformation at low pH al lowing the bound peptide to escape. In wildtype IEk, the need to protonate these amino acids also may be a bottleneck in the return to a closed confor mation after peptide binding.