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

Proteins. 2022 Sep;90(9):1645-1654. doi: 10.1002/prot.26343. Epub 2022 Apr 22.

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.

Keywords: T-cell receptor; binding; hotspot residues; hydrogen bond interactions; hydrophobic interactions; interaction energy; major histocompatibility complex; nonamer; peptide; ternary.

MeSH terms

  • HLA-A2 Antigen / chemistry
  • HLA-A2 Antigen / genetics
  • HLA-A2 Antigen / metabolism
  • Humans
  • Major Histocompatibility Complex
  • Peptides* / chemistry
  • Protein Binding
  • Receptors, Antigen, T-Cell* / genetics

Substances

  • HLA-A2 Antigen
  • Peptides
  • Receptors, Antigen, T-Cell