6BIV

HLA-DRB1 in complex with citrullinated LL37 peptide

Summary for 6BIV

• Entry DOI: 10.2210/pdb6biv/pdb
• Related: 6BIJ 6BIL 6BIN 6BIR
• Descriptor: HLA class II histocompatibility antigen, DR alpha chain, HLA class II histocompatibility antigen, DRB1-4 beta chain, LL37_Cit91, ... (5 entities in total)
• Functional Keywords: hla, mhc, citrulline, rheumatoid arthritis, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 47063.19

Authors

Ting, Y.T.,Scally, S.W.,Rossjohn, J. (deposition date: 2017-11-03, release date: 2018-01-17, Last modification date: 2024-10-16)

Primary citation

Ting, Y.T.,Petersen, J.,Ramarathinam, S.H.,Scally, S.W.,Loh, K.L.,Thomas, R.,Suri, A.,Baker, D.G.,Purcell, A.W.,Reid, H.H.,Rossjohn, J.
The interplay between citrullination and HLA-DRB1 polymorphism in shaping peptide binding hierarchies in rheumatoid arthritis.
J. Biol. Chem., 293:3236-3251, 2018

PubMed Abstract: The locus is strongly associated with rheumatoid arthritis (RA) susceptibility, whereupon citrullinated self-peptides bind to HLA-DR molecules bearing the shared epitope (SE) amino acid motif. However, the differing propensity for citrullinated/non-citrullinated self-peptides to bind given HLA-DR allomorphs remains unclear. Here, we used a fluorescence polarization assay to determine a hierarchy of binding affinities of 34 self-peptides implicated in RA against three HLA-DRB1 allomorphs (HLA-DRB1*04:01/*04:04/*04:05) each possessing the SE motif. For all three HLA-DRB1 allomorphs, we observed a strong correlation between binding affinity and citrullination at P4 of the bound peptide ligand. A differing hierarchy of peptide-binding affinities across the three HLA-DRB1 allomorphs was attributable to the β-chain polymorphisms that resided outside the SE motif and were consistent with sequences of naturally presented peptide ligands. Structural determination of eight HLA-DR4-self-epitope complexes revealed strict conformational convergence of the P4-Cit and surrounding HLA β-chain residues. Polymorphic residues that form part of the P1 and P9 pockets of the HLA-DR molecules provided a structural basis for the preferential binding of the citrullinated self-peptides to the HLA-DR4 allomorphs. Collectively, we provide a molecular basis for the interplay between citrullination of self-antigens and HLA polymorphisms that shape peptide-HLA-DR4 binding affinities in RA.

PubMed: 29317506
DOI: 10.1074/jbc.RA117.001013

Experimental method

X-RAY DIFFRACTION (2.9 Å)