The Three-Dimensional Structure of Peptide-MHC Complexes

Abstract

The ability of MHC molecules to present a broad spectrum of peptide antigens for T cell recognition requires a compromise between high affinity and broad specificity. Three-dimensional atomic structures of several class I and class II MHC molecules reveal a unique structural solution to this problem: Tight binding to the peptide main chain is supplemented by more or less restrictive interactions with peptide side chains. In spite of these contacts, peptide side-chain and conformational variability ensures that the resulting peptide-MHC complex presents an antigenically unique surface to T cell receptors. Extension of this understanding to other peptide-MHC complexes, including agonist/antagonist peptides and the identification of antigenic peptides within protein sequences, however, requires a detailed analysis of the interactions that determine both peptide-MHC binding affinity and the conformations of bound peptides. While many of these interactions can be modeled by homology with known structures, their specificity can depend sensitively on subtle and long-range structural effects. Structurally and immunologically important distinctions are also found between the class I and class II peptide-binding strategies. Taken together, these interactions ultimately determine the ability of an individual to respond successfully to immune challenges.

A marker for Stevens-Johnson syndrome …: ethnicity matters

“…12 The peptide specificity of a given HLA molecule resides in its binding groove, lined with different pockets that engage specific side chains of the peptide ligands. 13 HLA genes are extremely polymorphic and they encode proteins which play a crucial role in immunity. However, not all genetically different molecules are functionally different, and it is possible to group them into supertypes on the basis of their functional binding properties.…”

HLA-associated susceptibility to childhood B-cell precursor ALL: definition and role of HLA-DPB1 supertypes

“…Selective peptide binding by HLA allotypes is a prerequisite for the recognition of antigens by T cells leading to adaptive immunity (Madden, 1995). Such a mechanism may underpin the immunemediated progression of pre-ALL to overt leukaemia following delayed postnatal infection (Greaves, 2006).…”

Production and crystallization of MHC class I B allele single peptide complexes

“…The first class I structure, HLA A2 [4], together with subseqtlent structural analysis of other human class I alleles [5][6][7][8][9][10][11] aad murine alleles [12][13][14][15] complexed with single peptides, revealed general principles for peptide binding to class I molemles. These structures show that peptides are held in the class I binding groove at the N-and C-termini by a conserved network of hydrogen bonds and by the binding of conserved rcsidues (anchor residues) in pockets lined by polymorphic /~HC residues (review [16]). …”