5JLZ: Crystal Structure Of Hla-drb1*04:01 In Complex With Modified Alpha- Enolase Peptide 26-40 With Citrulline At The Position 32

Antibodies to citrullinated proteins, common in rheumatoid arthritis (RA) patients, are strongly associated to a specific set of HLA-DR alleles including HLA-DRB1*04:01, *04:04, and *01:01. Here, we first demonstrate that autoantibody levels toward the dominant citrullinated B cell epitope from alpha-enolase are significantly elevated in HLA-DRB1*04:01-positive RA patients. Furthermore, we identified alpha-enolase-derived T cell epitopes and demonstrated that native and citrullinated versions of several peptides bind with different affinities to HLA-DRB1*04:01, *04:04, and *01:01. The citrulline residues in the eight identified peptides are distributed throughout the entire length of the presented epitopes and more specifically, localized at peptide positions p-2, p2, p4, p6, p7, p10, and p11. Importantly, in contrast to its native version peptide 26 (TSKGLFRAAVPSGAS), the HLA-DRB1*04:01-restricted citrullinated peptide Cit26 (TSKGLFCitAAVPSGAS) elicited significant functional T cell responses in primary cells from RA patients. Comparative analysis of the crystal structures of HLA-DRB1*04:01 in complex with peptide 26 or Cit26 demonstrated that the posttranslational modification did not alter the conformation of the peptide. And since citrullination is the only structural difference between the two complexes, this indicates that the neo-antigen Cit26 is recognized by T cells with high specificity to the citrulline residue.
PDB ID: 5JLZDownload
MMDB ID: 145453
PDB Deposition Date: 2016/4/28
Updated in MMDB: 2016/12
Experimental Method:
x-ray diffraction
Resolution: 1.99  Å
Source Organism:
Similar Structures:
Biological Unit for 5JLZ: trimeric; determined by author and by software (PISA)
Molecular Components in 5JLZ
Label Count Molecule
Proteins (3 molecules)
HLA Class II Histocompatibility Antigen, DR Alpha Chain(Gene symbol: HLA-DRA)
Molecule annotation
HLA Class II Histocompatibility Antigen, Drb1-4 Beta Chain(Gene symbol: HLA-DRB4)
Molecule annotation
Molecule annotation
* Click molecule labels to explore molecular sequence information.

Citing MMDB