Peptide-binding motifs define the functional architecture of human leukocyte antigens.

Peptide-binding motifs define 40 functional groups across 155 class I and 93 class II HLA allotypes, with within-group molecules showing higher immunopeptidome similarity than across groups.

• Why it matters: HLA polymorphism creates allele-specific peptide-binding motifs, but the global functional “architecture” linking motif diversity to immunopeptidome variation is not well resolved.
• What they did: Using large-scale immunopeptidomics, the study derived PBMs from public resources and performed de novo motif deconvolution of 334,089 class II peptides, then used hierarchical clustering to define groups.
• The result: PBM groups only partially matched serological antigen groups and evolutionary divergence metrics, yet captured immunopeptidome differences with higher resolution than existing sequence- or epitope-based models.

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