5C0A

1E6 TCR in complex with HLA-A02 carrying MVW peptide

Summary for 5C0A

• Entry DOI: 10.2210/pdb5c0a/pdb
• Related: 3UTP 3UTQ 3UTS 3UTT 5C06 5C07 5C08 5C09 5C0B 5C0C 5C0D 5C0E 5C0F 5C0G 5C0H 5C0I 5C0J 5HYJ
• Descriptor: HLA class I histocompatibility antigen, A-2 alpha chain, Beta-2-microglobulin, Marker peptide, ... (9 entities in total)
• Functional Keywords: immuno, hla-a02, 1e6-tcr, cross-reactivity, immune system
• Biological source: Homo sapiens (Human); More
• Cellular location: Membrane; Single-pass type I membrane protein: P01892; Secreted : P61769
• Total number of polymer chains: 10
• Total formula weight: 192507.98

Authors

Rizkallah, P.J.,Bulek, A.M.,Cole, D.K.,Sewell, A.K. (deposition date: 2015-06-12, release date: 2016-05-04, Last modification date: 2024-10-16)

Primary citation

Cole, D.K.,Bulek, A.M.,Dolton, G.,Schauenberg, A.J.,Szomolay, B.,Rittase, W.,Trimby, A.,Jothikumar, P.,Fuller, A.,Skowera, A.,Rossjohn, J.,Zhu, C.,Miles, J.J.,Peakman, M.,Wooldridge, L.,Rizkallah, P.J.,Sewell, A.K.
Hotspot autoimmune T cell receptor binding underlies pathogen and insulin peptide cross-reactivity.
J.Clin.Invest., 126:2191-2204, 2016

PubMed Abstract: The cross-reactivity of T cells with pathogen- and self-derived peptides has been implicated as a pathway involved in the development of autoimmunity. However, the mechanisms that allow the clonal T cell antigen receptor (TCR) to functionally engage multiple peptide-major histocompatibility complexes (pMHC) are unclear. Here, we studied multiligand discrimination by a human, preproinsulin reactive, MHC class-I-restricted CD8+ T cell clone (1E6) that can recognize over 1 million different peptides. We generated high-resolution structures of the 1E6 TCR bound to 7 altered peptide ligands, including a pathogen-derived peptide that was an order of magnitude more potent than the natural self-peptide. Evaluation of these structures demonstrated that binding was stabilized through a conserved lock-and-key-like minimal binding footprint that enables 1E6 TCR to tolerate vast numbers of substitutions outside of this so-called hotspot. Highly potent antigens of the 1E6 TCR engaged with a strong antipathogen-like binding affinity; this engagement was governed though an energetic switch from an enthalpically to entropically driven interaction compared with the natural autoimmune ligand. Together, these data highlight how T cell cross-reactivity with pathogen-derived antigens might break self-tolerance to induce autoimmune disease.

PubMed: 27183389
DOI: 10.1172/JCI85679

Experimental method

X-RAY DIFFRACTION (2.46 Å)