The crystal structures of class I major histocompatibility complex (MHC)
molecules complexed with antigenic peptides revealed a network of hydrogen bonds
between the charged amino- and carboxyl-termini of the peptides and conserved
MHC residues at both ends of the peptide binding site. These interactions were
shown to contribute substantially to the stability of class I MHC/peptide
complexes by thermal denaturation studies using synthetic peptides in which
either the amino- or carboxyl-terminal group is substituted by a methyl group.
Here we report crystal structures of HLA-A*0201 complexed with these terminally
modified synthetic peptides showing that they adopt the same bound conformation
as antigenic peptides. A number of variations in peptide conformation were
observed for the terminally modified peptides, including in one case, a large
conformational difference in four central peptide residues that is apparently
caused by the lattice contact. This is reminiscent of the way binding a T-cell
receptor changed the conformation of central residues of an MHC-bound peptide.
The structures determined identify which conserved hydrogen bonds are eliminated
in terminally substituted peptides and suggest an increased energetic importance
of the interactions at the peptide termini for MHC-peptide stability.
