Summary for 5N1Y
| Entry DOI | 10.2210/pdb5n1y/pdb |
| Related | 5C07 5C08 5C09 5C0A 5C0B 5C0D 5C0F 5C0G 5C0I 5C0J 5COD 5COE 5HYJ |
| Descriptor | HLA class I histocompatibility antigen, A-2 alpha chain, Beta-2-microglobulin, MVWGPDPLYV, ... (6 entities in total) |
| Functional Keywords | immuno, hla-a02, 1e6-tcr, cross-rteactivity, 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 |
| Total number of polymer chains | 3 |
| Total formula weight | 46127.31 |
| Authors | Rizkallah, P.J.,Bulek, A.M.,Cole, D.K.,Sewell, A.K. (deposition date: 2017-02-06, release date: 2017-02-15, Last modification date: 2024-11-20) |
| 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 Cited by 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: 27183389DOI: 10.1172/JCI85679 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.39 Å) |
Structure validation
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