Peptide binding to MHC class I is determined by individual pockets in the binding groove

T. E. Johansen, K. McCullough, B. Catipovic, X. M. Su, M. Amzel, J. P. Schneck

Research output: Contribution to journalArticlepeer-review


H-2K(b) and HLA-A2 are MHC4 class I molecules with a similar overall structure. Important differences between these two class I molecules reside in the structure of the individual pockets in the antigenic-peptide-binding groove. H-2K(b), which has a deep C pocket, binds specifically peptides with a tyrosine or a phenylalanine at position 5. In contrast, HLA-A2 has a shallow C pocket, which cannot accommodate large side chains at position 5. Site-directed mutagenesis was used to generate a chimera between the murine H-2K(b) and the human HLA-A2 [H-2K(b)/HLA-A2(C')]. The structure of this chimera is similar to H-2K(b) except for the region around the deep C pocket, where residues at positions 9, 97 and 99 were substituted with those bulkier residues from HLA-A2. Peptide binding between this chimera and H-2K(b)- binding peptides [VSV (52-59), OVA (257-264), and MCMV pp89 (168-176)], revealed that the deep C pocket of H-2K(b) was crucial for high-affinity binding. While a peptide, VSV (52-59), was found to bind with severalfold lower 'affinity' to H-2K(b)/HLA-A2(C') than to the wild-type H-2K(b), a VSV analogue with the tyrosine in position 5 (Tyr5) substituted with an alanine was found to bind with a similar 'affinity' to both MHC class I molecules. Computer-aided modelling of the H-2K(b)/HLA-A2(C') complex indicates that the VSV (52-59) peptide probably binds to the chimeric MHC molecule with the peptide side chain of anchor residue Tyr5 pointing away from the groove. These results confirm a role of the individual pockets in determining peptide-binding affinity and specificity and suggest that this may be accomplished by changes in side-chain orientation.

Original languageEnglish (US)
Pages (from-to)137-146
Number of pages10
JournalScandinavian Journal of Immunology
Issue number2
StatePublished - Jan 1 1997

ASJC Scopus subject areas

  • Immunology

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