PDBsum entry 4z76

Immune system

PDB id: 4z76

Contents

Protein chains

277 a.a.

100 a.a.

Ligands

LEU-TYR-LEU-VAL-CYS-GLY-GLU-ARG-VAL ×2

EDO ×6

GOL ×3

SO4 ×15

Waters ×465

PDB id:

4z76

Name:

Immune system

Title:

Weak tcr binding to an unstable insulin epitope drives type 1 diabetes

Structure:

H-2 class i histocompatibility antigen, k-d alpha chain. Chain: a, d. Fragment: unp residues 22-296. Synonym: leukocyte antigen heavy chain, h-2k(d). Engineered: yes. Beta-2-microglobulin. Chain: b, e. Fragment: unp residues 21-119. Engineered: yes.

Source:

Mus musculus. House mouse. Organism_taxid: 10090. Gene: h2-k1, h2-k. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Expression_system_variant: rosetta. Homo sapiens. Human.

Resolution:

1.88Å R-factor: 0.186 R-free: 0.230

Authors:

P.J.Rizkallah,D.K.Cole

Key ref:

C.Motozono et al. (2015). Distortion of the Major Histocompatibility Complex Class I Binding Groove to Accommodate an Insulin-derived 10-Mer Peptide. J Biol Chem, 290, 18924-18933. PubMed id: 26085090 DOI: 10.1074/jbc.M114.622522

Date:

06-Apr-15 Release date: 24-Jun-15

Protein chains

P01902  (HA1D_MOUSE) -  H-2 class I histocompatibility antigen, K-D alpha chain from Mus musculus

Seq: 368 a.a.

Struc: 277 a.a.*

Protein chains

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

Seq: 119 a.a.

Struc: 100 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

DOI no: 10.1074/jbc.M114.622522

J Biol Chem 290:18924-18933 (2015)

PubMed id: 26085090

Distortion of the Major Histocompatibility Complex Class I Binding Groove to Accommodate an Insulin-derived 10-Mer Peptide.

C.Motozono, J.A.Pearson, E.De Leenheer, P.J.Rizkallah, K.Beck, A.Trimby, A.K.Sewell, F.S.Wong, D.K.Cole.

ABSTRACT

The non-obese diabetic mouse model of type 1 diabetes continues to be an important tool for delineating the role of T-cell-mediated destruction of pancreatic β-cells. However, little is known about the molecular mechanisms that enable this disease pathway. We show that insulin reactivity by a CD8(+) T-cell clone, known to induce type 1 diabetes, is characterized by weak T-cell antigen receptor binding to a relatively unstable peptide-MHC. The structure of the native 9- and 10-mer insulin epitopes demonstrated that peptide residues 7 and 8 form a prominent solvent-exposed bulge that could potentially be the main focus of T-cell receptor binding. The C terminus of the peptide governed peptide-MHC stability. Unexpectedly, we further demonstrate a novel mode of flexible peptide presentation in which the MHC peptide-binding groove is able to "open the back door" to accommodate extra C-terminal peptide residues.