PDBsum entry 5c0c

Immune system

PDB id: 5c0c

Contents

Protein chains

276 a.a.

100 a.a.

200 a.a.

247 a.a.

Ligands

ARG-GLN-PHE-GLY-PRO-ASP-TRP-ILE-VAL-ALA ×2

EDO ×33

PG4 ×2

SO4 ×4

GOL ×3

Waters ×569

PDB id:

5c0c

Name:

Immune system

Title:

1e6 tcr in complex with hla-a02 carrying rqfgpdwiva

Structure:

Hla class i histocompatibility antigen, a-2 alpha chain. Chain: a, f. Fragment: unp residues 25-300. Synonym: mhc class i antigen a 2, Hla-a02 heavy chain. Engineered: yes. Beta-2-microglobulin. Chain: b, g. Fragment: unp residues 21-119. Engineered: yes.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: hla-a, hlaa. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: b2m, cdabp0092, hdcma22p. Synthetic: yes. Expression_system_taxid: 562

Resolution:

1.97Å R-factor: 0.190 R-free: 0.227

Authors:

P.J.Rizkallah,A.M.Bulek,D.K.Cole,A.K.Sewell

Key ref:

D.K.Cole et al. (2016). Hotspot autoimmune T cell receptor binding underlies pathogen and insulin peptide cross-reactivity. J Clin Invest, 126, 2191-2204. PubMed id: 27183389 DOI: 10.1172/JCI85679

Date:

12-Jun-15 Release date: 04-May-16

Protein chains

P04439  (1A03_HUMAN) -  HLA class I histocompatibility antigen, A alpha chain from Homo sapiens

Seq: 365 a.a.

Struc: 276 a.a.*

Protein chains

P61769  (B2MG_HUMAN) -  Beta-2-microglobulin from Homo sapiens

Seq: 119 a.a.

Struc: 100 a.a.*

Protein chains

A0A0B4J271  (TVAL3_HUMAN) -  T cell receptor alpha variable 12-3 from Homo sapiens

Seq: 114 a.a.

Struc: 200 a.a.*

Protein chains

P01848  (TCA_HUMAN) -  T cell receptor alpha chain constant from Homo sapiens

Seq: 140 a.a.

Struc: 200 a.a.*

Protein chains

A0A0B4J2E0  (A0A0B4J2E0_HUMAN) -  T cell receptor beta variable 12-4 from Homo sapiens

Seq: 115 a.a.

Struc: 247 a.a.*

Protein chains

A0A5B9  (TRBC2_HUMAN) -  T cell receptor beta constant 2 from Homo sapiens

Seq: 178 a.a.

Struc: 247 a.a.*

* PDB and UniProt seqs differ at 29 residue positions (black crosses)

DOI no: 10.1172/JCI85679

J Clin Invest 126:2191-2204 (2016)

PubMed id: 27183389

Hotspot autoimmune T cell receptor binding underlies pathogen and insulin peptide cross-reactivity.

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.

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.