HLA-DM recognizes the flexible conformation of major histocompatibility complex class II

DM facilitates formation of high affinity complexes of peptide-major histoc ompatibility complex (MHC) by release of class II MHC-associated invariant chain peptide (CLIP). This has been proposed to occur through discriminatio n of complex stability. By probing kinetic and conformational inter-mediate s of the wild-type and mutant human histocompatibility leukocyte antigen (H LA)-DR1-peptide complexes, and examining their reactivities with DM, we pro pose that DM interacts with the flexible hydrophobic pocket 1 of DR1 and co nverts the molecule into a conformation that is highly peptide receptive. A more rigid conformation, generated upon filling of pocket 1, is less susce ptible to DM effects. Thus, DM edits peptide-MHC by recognition of the flex ibility rather than stability of the complex.