4QOK

Structural basis for ineffective T-cell responses to MHC anchor residue improved heteroclitic peptides

Summary for 4QOK

• Entry DOI: 10.2210/pdb4qok/pdb
• Related: 3HG1 4JFD
• Descriptor: HLA class I histocompatibility antigen, A-2 alpha chain, Beta-2-microglobulin, Melanoma antigen recognized by T-cells 1 marker peptide, ... (7 entities in total)
• Functional Keywords: immunoglobulin, hla, tcr, melanoma, immune system
• Biological source: Homo sapiens (human); More
• Cellular location: Membrane; Single-pass type I membrane protein: P01892; Secreted . Note=(Microbial infection) In the presence of M: P61769; Endoplasmic reticulum membrane; Single-pass type III membrane protein: Q16655
• Total number of polymer chains: 5
• Total formula weight: 93657.81

Authors

Rizkallah, P.J.,Cole, D.K.,Madura, F.,Sewell, A.K. (deposition date: 2014-06-20, release date: 2014-12-17, Last modification date: 2024-10-30)

Primary citation

Madura, F.,Rizkallah, P.J.,Holland, C.J.,Fuller, A.,Bulek, A.,Godkin, A.J.,Schauenburg, A.J.,Cole, D.K.,Sewell, A.K.
Structural basis for ineffective T-cell responses to MHC anchor residue-improved "heteroclitic" peptides.
Eur.J.Immunol., 45:584-591, 2015

PubMed Abstract: MHC anchor residue-modified "heteroclitic" peptides have been used in many cancer vaccine trials and often induce greater immune responses than the wild-type peptide. The best-studied system to date is the decamer MART-1/Melan-A26-35 peptide, EAAGIGILTV, where the natural alanine at position 2 has been modified to leucine to improve human leukocyte antigen (HLA)-A*0201 anchoring. The resulting ELAGIGILTV peptide has been used in many studies. We recently showed that T cells primed with the ELAGIGILTV peptide can fail to recognize the natural tumor-expressed peptide efficiently, thereby providing a potential molecular reason for why clinical trials of this peptide have been unsuccessful. Here, we solved the structure of a TCR in complex with HLA-A*0201-EAAGIGILTV peptide and compared it with its heteroclitic counterpart , HLA-A*0201-ELAGIGILTV. The data demonstrate that a suboptimal anchor residue at position 2 enables the TCR to "pull" the peptide away from the MHC binding groove, facilitating extra contacts with both the peptide and MHC surface. These data explain how a TCR can distinguish between two epitopes that differ by only a single MHC anchor residue and demonstrate how weak MHC anchoring can enable an induced-fit interaction with the TCR. Our findings constitute a novel demonstration of the extreme sensitivity of the TCR to minor alterations in peptide conformation.

PubMed: 25471691
DOI: 10.1002/eji.201445114

Experimental method

X-RAY DIFFRACTION (3 Å)