PDBsum entry 4md4

Immune system

PDB id: 4md4

Contents

Protein chains

182 a.a.

189 a.a.

13 a.a.

Ligands

NAG-NAG

NAG ×2

EDO ×3

Waters ×470

PDB id:

4md4

Name:

Immune system

Title:

Immune receptor

Structure:

Hla class ii histocompatibility antigen, dr alpha chain. Chain: a. Fragment: extracellular domain, unp residues 26-206. Synonym: mhc class ii antigen dra. Engineered: yes. Hla class ii histocompatibility antigen, drb1-4 beta chain. Chain: b. Fragment: extracellular domain, unp residues 30-219. Synonym: mhc class ii antigen drb1 4, Dr-4, dr4.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: hla-dra, hla-dra1. Expressed in: homo sapiens. Expression_system_taxid: 9606. Gene: hla-drb1. Synthetic: yes. Other_details: this sequence is from human aggrecan and contains

Resolution:

1.95Å R-factor: 0.167 R-free: 0.209

Authors:

S.W.Scally,J.Rossjohn

Key ref:

S.W.Scally et al. (2013). A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis. J Exp Med, 210, 2569-2582. PubMed id: 24190431 DOI: 10.1084/jem.20131241

Date:

22-Aug-13 Release date: 04-Dec-13

Protein chain

P01903  (DRA_HUMAN) -  HLA class II histocompatibility antigen, DR alpha chain from Homo sapiens

Seq: 254 a.a.

Struc: 182 a.a.*

Protein chain

P01911  (2B1F_HUMAN) -  HLA class II histocompatibility antigen, DRB1 beta chain from Homo sapiens

Seq: 266 a.a.

Struc: 189 a.a.*

Protein chain

P16112  (PGCA_HUMAN) -  Aggrecan core protein from Homo sapiens

Seq: 2530 a.a.

Struc: 13 a.a.*

* PDB and UniProt seqs differ at 23 residue positions (black crosses)

DOI no: 10.1084/jem.20131241

J Exp Med 210:2569-2582 (2013)

PubMed id: 24190431

A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis.

S.W.Scally, J.Petersen, S.C.Law, N.L.Dudek, H.J.Nel, K.L.Loh, L.C.Wijeyewickrema, S.B.Eckle, J.van Heemst, R.N.Pike, J.McCluskey, R.E.Toes, N.L.La Gruta, A.W.Purcell, H.H.Reid, R.Thomas, J.Rossjohn.

ABSTRACT

Rheumatoid arthritis (RA) is strongly associated with the human leukocyte antigen (HLA)-DRB1 locus that possesses the shared susceptibility epitope (SE) and the citrullination of self-antigens. We show how citrullinated aggrecan and vimentin epitopes bind to HLA-DRB1*04:01/04. Citrulline was accommodated within the electropositive P4 pocket of HLA-DRB1*04:01/04, whereas the electronegative P4 pocket of the RA-resistant HLA-DRB1*04:02 allomorph interacted with arginine or citrulline-containing epitopes. Peptide elution studies revealed P4 arginine-containing peptides from HLA-DRB1*04:02, but not from HLA-DRB1*04:01/04. Citrullination altered protease susceptibility of vimentin, thereby generating self-epitopes that are presented to T cells in HLA-DRB1*04:01(+) individuals. Using HLA-II tetramers, we observed citrullinated vimentin- and aggrecan-specific CD4(+) T cells in the peripheral blood of HLA-DRB1*04:01(+) RA-affected and healthy individuals. In RA patients, autoreactive T cell numbers correlated with disease activity and were deficient in regulatory T cells relative to healthy individuals. These findings reshape our understanding of the association between citrullination, the HLA-DRB1 locus, and T cell autoreactivity in RA.