5MZM

Structure of H-2Db in complex with TEIPP APL Trh4 p3P

Summary for 5MZM

• Entry DOI: 10.2210/pdb5mzm/pdb
• Descriptor: H-2 class I histocompatibility antigen, D-B alpha chain, Beta-2-microglobulin, Ceramide synthase 5 derived peptide Trh4 p3P, ... (6 entities in total)
• Functional Keywords: cancer, neo-epitope, t-cell epitopes associated with impaired peptide processing, mhc-i, immune system
• Biological source: Mus musculus (Mouse); More
• Cellular location: Membrane; Single-pass type I membrane protein: P01899; Secreted: P01887
• Total number of polymer chains: 6
• Total formula weight: 89949.08

Authors

Hafstrand, I.,Achour, A.,Sandalova, T. (deposition date: 2017-02-01, release date: 2018-03-21, Last modification date: 2024-11-06)

Primary citation

Hafstrand, I.,Doorduijn, E.M.,Sun, R.,Talyzina, A.,Sluijter, M.,Pellegrino, S.,Sandalova, T.,Duru, A.D.,van Hall, T.,Achour, A.
The Immunogenicity of a Proline-Substituted Altered Peptide Ligand toward the Cancer-Associated TEIPP Neoepitope Trh4 Is Unrelated to Complex Stability.
J. Immunol., 200:2860-2868, 2018

PubMed Abstract: Human cancers frequently display defects in Ag processing and presentation allowing for immune evasion, and they therefore constitute a significant challenge for T cell-based immunotherapy. We have previously demonstrated that the antigenicity of tumor-associated Ags can be significantly enhanced through unconventional residue modifications as a novel tool for MHC class I (MHC-I)-based immunotherapy approaches. We have also previously identified a novel category of cancer neo-epitopes, that is, T cell epitopes associated with impaired peptide processing (TEIPP), that are selectively presented by MHC-I on cells lacking the peptide transporter TAP. In this study, we demonstrate that substitution of the nonanchoring position 3 into a proline residue of the first identified TEIPP peptide, the murine Trh4, results in significantly enhanced recognition by antitumor CTLs toward the wild-type epitope. Although higher immunogenicity has in most cases been associated with increased MHC/peptide complex stability, our results demonstrate that the overall stability of H-2D in complex with the highly immunogenic altered peptide ligand Trh4-p3P is significantly reduced compared with wild-type H-2D/Trh4. Comparison of the crystal structures of the H-2D/Trh4-p3P and H-2D/Trh4 complexes revealed that the conformation of the nonconventional methionine anchor residue p5M is altered, deleting its capacity to form adequate sulfur-π interactions with H-2D residues, thus reducing the overall longevity of the complex. Collectively, our results indicate that vaccination with Thr4-p3P significantly enhances T cell recognition of targets presenting the wild-type TEIPP epitope and that higher immunogenicity is not necessarily directly related to MHC/peptide complex stability, opening for the possibility to design novel peptide vaccines with reduced MHC/peptide complex stability.

PubMed: 29507106
DOI: 10.4049/jimmunol.1700228

Experimental method

X-RAY DIFFRACTION (2.4 Å)