Zooming in on the hydrophobic ridge of H-2D(b): Implications for the conformational variability of bound peptides

Class I major histocompatibility complex (MHC) molecules, which display int racellularly processed peptides on the cell surface for scanning by T-cell receptors (TCRs), are extraordinarily polymorphic. MHC polymorphism is beli eved to result from natural selection, since individuals heterozygous at th e corresponding loci can cope with a larger number of pathogens. Here, we p resent the crystal structures of the murine MHC molecule H-2D(b) in complex with the peptides gp276 and np396 from the lymphocytic choriomeningitis vi rus (LCMV), solved at 2.18 Angstrom and 2.20 Angstrom resolution, respectiv ely. The most prominent feature of H-2D(b) is a hydrophobic ridge that cuts across its antigen-binding site, which is conserved in the L-d-like family of class I MHC molecules. The comparison with previously solved crystal st ructures of peptide/H-2D(b) complexes shows that the hydrophobic ridge focu ses the conformational variability of the bound peptides in a "hot-spot", w hich could allow optimal TCR interaction and discrimination. This finding s uggests a functional reason for the conservation of this structural element . (C) 2001 Academic Press.