5E8N

The structure of the TEIPP associated Trh4 peptide in complex with H-2D(b)

Summary for 5E8N

• Entry DOI: 10.2210/pdb5e8n/pdb
• Descriptor: H-2 class I histocompatibility antigen, D-B alpha chain, Beta-2-microglobulin, Ceramide synthase 5, ... (6 entities in total)
• Functional Keywords: cancer, neo-epitope, tap-deficiency, teipp, mhc-i, sulfur-pi interactions, non-classical peptide binding, immune system
• Biological source: Mus musculus (House Mouse); More
• Cellular location: Membrane; Single-pass type I membrane protein: P01899; Secreted: P01887; Nucleus membrane ; Multi-pass membrane protein : Q9D6K9
• Total number of polymer chains: 12
• Total formula weight: 179582.05

Authors

Hafstrand, I.,Doorduijn, E.,Duru, A.D.,Buratto, J.,Oliveira, C.C.,Sandalova, T.,van Hall, T.,Achour, A. (deposition date: 2015-10-14, release date: 2016-02-03, Last modification date: 2024-11-20)

Primary citation

Hafstrand, I.,Doorduijn, E.M.,Duru, A.D.,Buratto, J.,Oliveira, C.C.,Sandalova, T.,van Hall, T.,Achour, A.
The MHC Class I Cancer-Associated Neoepitope Trh4 Linked with Impaired Peptide Processing Induces a Unique Noncanonical TCR Conformer.
J Immunol., 196:2327-2334, 2016

PubMed Abstract: MHC class I downregulation represents a significant challenge for successful T cell-based immunotherapy. T cell epitopes associated with impaired peptide processing (TEIPP) constitute a novel category of immunogenic Ags that are selectively presented on transporter associated with Ag processing-deficient cells. The TEIPP neoepitopes are CD8 T cell targets, derived from nonmutated self-proteins that might be exploited to prevent immune escape. In this study, the crystal structure of H-2D(b) in complex with the first identified TEIPP Ag (MCLRMTAVM) derived from the Trh4 protein has been determined to 2.25 Å resolution. In contrast to prototypic H-2D(b) peptides, Trh4 takes a noncanonical peptide-binding pattern with extensive sulfur-π interactions that contribute to the overall complex stability. Importantly, the noncanonical methionine at peptide position 5 acts as a main anchor, altering only the conformation of the H-2D(b) residues Y156 and H155 and thereby forming a unique MHC/peptide conformer that is essential for recognition by TEIPP-specific T cells. Substitution of peptide residues p2C and p5M to the conservative α-aminobutyric acid and norleucine, respectively, significantly reduced complex stability, without altering peptide conformation or T cell recognition. In contrast, substitution of p5M to a conventional asparagine abolished recognition by the H-2D(b)/Trh4-specific T cell clone LnB5. We anticipate that the H-2D(b)/Trh4 complex represents the first example, to our knowledge, of a broader repertoire of alternative MHC class I binders.

PubMed: 26800871
DOI: 10.4049/jimmunol.1502249

Experimental method

X-RAY DIFFRACTION (2.25 Å)