7T6I

Crystal structure of HLA-DP1 in complex with pp65 peptide in reverse orientation

Summary for 7T6I

• Entry DOI: 10.2210/pdb7t6i/pdb
• Descriptor: HLA class II histocompatibility antigen DP alpha chain, MHC class II antigen, pp65 peptide, ... (7 entities in total)
• Functional Keywords: antigen presentation, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 45847.97

Authors

Lim, J.J.,Reid, H.,Rossjohn, J. (deposition date: 2021-12-13, release date: 2022-12-07, Last modification date: 2024-11-13)

Primary citation

Klobuch, S.,Lim, J.J.,van Balen, P.,Kester, M.G.D.,de Klerk, W.,de Ru, A.H.,Pothast, C.R.,Jedema, I.,Drijfhout, J.W.,Rossjohn, J.,Reid, H.H.,van Veelen, P.A.,Falkenburg, J.H.F.,Heemskerk, M.H.M.
Human T cells recognize HLA-DP-bound peptides in two orientations.
Proc.Natl.Acad.Sci.USA, 119:e2214331119-e2214331119, 2022

PubMed Abstract: Human leukocyte antigen (HLA) molecules present small peptide antigens to T cells, thereby allowing them to recognize pathogen-infected and cancer cells. A central dogma over the last 50+ y is that peptide binding to HLA molecules is mediated by the docking of side chains of particular amino acids in the peptide into pockets in the HLA molecules in a conserved N- to C-terminal orientation. Whether peptides can be presented in a reversed C- to N-terminal orientation remains unclear. Here, we performed large-scale identification of peptides bound to HLA-DP molecules and observed that in addition to peptide binding in an N- to C-terminal orientation, in 9 out of 14 HLA-DP allotypes, reverse motifs are found, compatible with C- to N-terminal peptide binding. Moreover, we isolated high-avidity human cytomegalovirus (CMV)-specific HLA-DP-restricted CD4 T cells from the memory repertoire of healthy donors and demonstrate that such T cells recognized CMV-derived peptides bound to HLA-DPB1*01:01 or *05:01 in a reverse C- to N-terminal manner. Finally, we obtained a high-resolution HLA-DPB1*01:01-CMVpp65 peptide crystal structure, which is the molecular basis for C- to N-terminal peptide binding to HLA-DP. Our results point to unique features of HLA-DP molecules that substantially broaden the HLA class II bound peptide repertoire to combat pathogens and eliminate cancer cells.

PubMed: 36442096
DOI: 10.1073/pnas.2214331119

Experimental method

X-RAY DIFFRACTION (2.3 Å)