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PDBsum entry 5c0c
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Immune system
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PDB id
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5c0c
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Contents |
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276 a.a.
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100 a.a.
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200 a.a.
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247 a.a.
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References listed in PDB file
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Key reference
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Title
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Hotspot autoimmune t cell receptor binding underlies pathogen and insulin peptide cross-Reactivity.
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Authors
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D.K.Cole,
A.M.Bulek,
G.Dolton,
A.J.Schauenberg,
B.Szomolay,
W.Rittase,
A.Trimby,
P.Jothikumar,
A.Fuller,
A.Skowera,
J.Rossjohn,
C.Zhu,
J.J.Miles,
M.Peakman,
L.Wooldridge,
P.J.Rizkallah,
A.K.Sewell.
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Ref.
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J Clin Invest, 2016,
126,
2191-2204.
[DOI no: ]
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PubMed id
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Abstract
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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.
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