Hla-Dm Recognizes the Flexible Conformation of Major Histocompatibility Complex Class II

DM facilitates formation of high affinity complexes of peptide–major histocompatibility complex (MHC) by release of class II MHC–associated invariant chain peptide (CLIP). This has been proposed to occur through discrimination of complex stability. By probing kinetic and conformational intermediates of the wild-type and mutant human histocompatibility leukocyte antigen (HLA)-DR1–peptide complexes, and examining their reactivities with DM, we propose that DM interacts with the flexible hydrophobic pocket 1 of DR1 and converts the molecule into a conformation that is highly peptide receptive. A more rigid conformation, generated upon filling of pocket 1, is less susceptible to DM effects. Thus, DM edits peptide–MHC by recognition of the flexibility rather than stability of the complex.