6Z9X

Human Class I Major Histocompatibility Complex, A02 allele, presenting LLS (t-butyl)Y FGTPT

Summary for 6Z9X

• Entry DOI: 10.2210/pdb6z9x/pdb
• Descriptor: MHC class I antigen, Beta-2-microglobulin, LEU-LEU-SER-TUR-PHE-GLY-THR-PRO-THR, ... (5 entities in total)
• Functional Keywords: mhc i, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 90154.07

Authors

Rizkallah, P.J.,Man, S.,Redman, J.E. (deposition date: 2020-06-04, release date: 2021-06-30, Last modification date: 2024-07-10)

Primary citation

Man, S.,Redman, J.E.,Cross, D.L.,Cole, D.K.,Can, I.,Davies, B.,Hashimdeen, S.S.,Reid, R.,Llewellyn-Lacey, S.,Miners, K.L.,Ladell, K.,Lissina, A.,Brown, P.E.,Wooldridge, L.,Price, D.A.,Rizkallah, P.J.
Synthetic Peptides with Inadvertent Chemical Modifications Can Activate Potentially Autoreactive T Cells.
J Immunol., 207:1009-1017, 2021

PubMed Abstract: The human CD8 T cell clone 6C5 has previously been shown to recognize the -butyl-modified Bax peptide LLSY(3-Bu)FGTPT presented by HLA-A*02:01. This nonnatural epitope was likely created as a by-product of fluorenylmethoxycarbonyl protecting group peptide synthesis and bound poorly to HLA-A*02:01. In this study, we used a systematic approach to identify and characterize natural ligands for the 6C5 TCR. Functional analyses revealed that 6C5 T cells only recognized the LLSYFGTPT peptide when Bu was added to the tyrosine residue and did not recognize the LLSYFGTPT peptide modified with larger (di-Bu) or smaller chemical groups (Me). Combinatorial peptide library screening further showed that 6C5 T cells recognized a series of self-derived peptides with dissimilar amino acid sequences to LLSY(3-Bu)FGTPT. Structural studies of LLSY(3-Bu)FGTPT and two other activating nonamers (IIGWMWIPV and LLGWVFAQV) in complex with HLA-A*02:01 demonstrated similar overall peptide conformations and highlighted the importance of the position (P) 4 residue for T cell recognition, particularly the capacity of the bulky amino acid tryptophan to substitute for the Bu-modified tyrosine residue in conjunction with other changes at P5 and P6. Collectively, these results indicated that chemical modifications directly altered the immunogenicity of a synthetic peptide via molecular mimicry, leading to the inadvertent activation of a T cell clone with unexpected and potentially autoreactive specificities.

PubMed: 34321228
DOI: 10.4049/jimmunol.2000756

Experimental method

X-RAY DIFFRACTION (2.68 Å)