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The HLA-DRB1 locus is strongly associated with rheumatoid arthritis (RA) susceptibility, whereupon citrullinated selfpeptides bind to HLA-DR molecules bearing the shared epitope (SE) amino acid motif. However, the differing propensity for citrullinated/noncitrullinated self-peptides to bind given HLA-DR allomorphs remains unclear. Here, we used a fluorescence polarisation 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 b-chain polymorphisms that resided outside the SE motif and were consistent with sequences of naturally presented peptide ligands. Structure determination of eight HLA-DR4-self-epitope complexes revealed strict conformational convergence of the P4-Cit and surrounding HLA b-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 selfpeptides 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. Sources for the primary RA-associated autoantigens may be from the site of disease including articular cartilage and synovial fluids (12-14) but others may be derived from blood plasma or surrounding mucosal tissues that are susceptible to inflammation (2). These proteins could undergo PTMs during numerous physiologic processes including infection, apoptosis and cellular stress. Some of the best-characterised autoantigens that bind ACPAs are citrullinated vimentin, fibrinogen, α-enolase and Type II collagen, which are present at high levels in the joint synovium (3,15).One of the key inherited risk factors that contribute to ACPA positive RA is the human leukocyte antigen (HLA) class II loci, namely HLA-DRB1, which encodes the HLA class II antigen presenting molecules (16-21). The antigen-binding groove of the HLA class II molecule can accommodate peptide ligands that vary in length, but the main pockets that interact most strongly with the bound peptide are P1, P4, P6, P7 and P9, which can accommodate the side chains of the peptide residues 1, 4, 6, 7 and 9 (22,23). A conserved amino acid sequence QKRAA, QRRAA, or RRRAA in position 70-74 of the HLA-DRB1 chain, known as the shared epitope (SE) motif, is highly prevalent (~90%) among ACPA seropositive patients (11,16). This SE motif defines the P4 pocket of the high-risk HLA-DRB1 RA-associated allomorphs. Subsequent GWAS studies have shown that two polymorphisms encoding β-chain residues at positions 11 and 13 at the base of the P4 pocket are also strongly associated with RA susceptibility (16)....

Streptococcus mutans UA159, the genome sequence reference strain, exhibits nonlantibiotic mutacin activity. In this study, bioinformatic and mutational analyses were employed to demonstrate that the antimicrobial repertoire of strain UA159 includes mutacin IV (specified by the nlm locus) and a newly identified bacteriocin, mutacin V (encoded by SMU.1914c).