Structural patterns in class 1 major histocompatibility complex‐restricted nonamer peptide binding to T‐cell receptors

Abstract

The startling diversity in αβ T‐cell receptor (TCR) sequences and structures complicates molecular‐level analyses of the specificity and sensitivity determining T‐cell immunogenicity. A number of three‐dimensional (3D) structures are now available of ternary complexes between TCRs and peptides: major histocompatibility complexes (pMHC). Here, to glean molecular‐level insights we analyze structures of TCRs bound to human class I nonamer peptide–MHC complexes. Residues at peptide positions 4–8 are found to be particularly important for TCR binding. About 90% of the TCRs hydrogen bond with one or both of the peptide residues at positions 4 and 8 presented by MHC allele HLA‐A2, and this number is still ~79% for peptides presented by other MHC alleles. Residue 8, which lies outside the previously‐identified central peptide region, is crucial for TCR recognition of class I MHC‐presented nonamer peptides. The statistics of the interactions also sheds light on the MHC residues important for TCR binding. The present analysis will aid in the structural modeling of TCR:pMHC complexes and has implications for the rational design of peptide‐based vaccines and T‐cell‐based immunotherapies.