Zooming in on the hydrophobic ridge of H-2Db: implications for the conformational variability of bound peptides

Class I major histocompatibility complex (MHC) molecules, which display intracellularly processed peptides on the cell surface for scanning by T-cell receptors (TCRs), are extraordinarily polymorphic. MHC polymorphism is believed to result from natural selection, since individuals heterozygous at the corresponding loci can cope with a larger number of pathogens. Here, we present the crystal structures of the murine MHC molecule H-2Db in complex with the peptides gp276 and np396 from the lymphocytic choriomeningitis virus (LCMV), solved at 2.18 Å and 2.20 Å resolution, respectively. The most prominent feature of H-2Db is a hydrophobic ridge that cuts across its antigen-binding site, which is conserved in the Ld-like family of class I MHC molecules. The comparison with previously solved crystal structures of peptide/H-2Db complexes shows that the hydrophobic ridge focuses the conformational variability of the bound peptides in a “hot-spot”, which could allow optimal TCR interaction and discrimination. This finding suggests a functional reason for the conservation of this structural element.