The pleiotropic pro-inflammatory cytokine interleukin (IL)-1β has co-evolved with a competitive inhibitor, IL-1 receptor antagonist (IL-1Ra). IL-1β initiates cell signaling by binding the IL-1 receptor (IL-1R) whereas IL-1Ra acts as an antagonist, blocking receptor signaling. The current paradigm for agonist/antagonist functions for these two proteins is based on the receptor-ligand interaction observed in the crystal structures of the receptor-ligand complexes. While IL-1Ra and IL-1β are structurally homologous, IL-1Ra engages only two of the three extracellular domains of the receptor, whereas IL-1β engages all three. We find that an allosteric functional switch exists within a highly conserved pocket of residues, residues 111-120. This region is maintained across all IL-1 family members and serves as a hydrophobic mini-core for IL-1β folding. A key difference across species is a conserved aromatic residue at position 117 in IL-1β, versus a conserved cysteine in IL-1Ra at the analogous position, 116. We find that the replacement of C116 with a phenylalanine switches the protein from an antagonist to an agonist despite the distant location of C116 relative to receptor interaction sites. These results suggest new ways to develop designer cytokine activity into the β-trefoil fold and may be of general use in regulation of this large family of signaling proteins. © 2013 Elsevier Ltd. All rights reserved.
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