Structural Features Impose Tight Peptide Binding Specificity in the Nonclassical MHC Molecule HLA-E

The crystal structure of the nonclassical human class Ib MHC molecule HLA-E has been determined in complex with a prototypic ligand, the nonamer peptide (VMAPRTVLL), derived from the highly conserved residues 3–11 of the human MHC class Ia leader sequence. The mode of peptide binding retains some of the standard features observed in MHC class Ia complexes, but novel features imply that HLA-E has evolved to mediate specific binding to a tightly defined set of almost identical hydrophobic peptides from the highly conserved class I leader sequences. These molecular adaptations make HLA-E a rigorous checkpoint at the cell surface reporting on the integrity of the antigen processing pathway to CD94/NKG2 receptor–bearing natural killer cells.