Interleukin‐1α, interleukin‐1β and interleukin‐1 receptor antagonist share a common U‐shaped recognition epitope on interleukin‐1 receptor surface

Abstract

Interleukin‐1 (IL‐1) plays a central role in the regulation of immune and inflammatory responses. There are two forms of IL‐1 agonists (IL‐1α and IL‐1β) and one form of IL‐1 antagonist (IL‐1Ra); they share a similar binding mode to the IL‐1 receptor (IL‐1R) but exhibit opposite biological functions on the receptor. In this study, the intermolecular interactions of IL‐1R receptors with IL‐1α, IL‐1β and IL‐1Ra ligands were systematically investigated at structural, energetic and dynamic levels. It was found that the receptor primarily adopts a U‐shaped, double‐stranded and linear/conformational‐hybrid epitope to commonly interact with the three ligands. The epitope covers a common protein segment (residues 107‐127), which is fully located within the C2T2 subdomain of the IL‐1R extracellular domain and contributes ~40% to the total binding energy of IL‐1R/ligand association. The epitope is natively folded into an ordered conformation in the IL‐1R protein context but would become largely disordered out of the context. Here, we adopted a disulfide bridge to staple U‐shaped epitope‐derived peptides, which can be effectively constrained into a native‐like conformation and thus exhibit an improved affinity to ligands as compared to their unstapled counterpart, with affinity increase by up to ~15‐fold. These disulfide bridges were designed to point out of ligand/peptide complex interface and thus would not disrupt the direct complex interaction. Energetic decomposition imparted that the stapling has only a modest influence on the interaction enthalpy and desolvation effect of ligand/peptide binding, but can substantially reduce entropy penalty upon the binding. For a peptide, the stapling‐addressed entropic reduction can be roughly regarded as a constant, which only improves peptide affinity to these ligands, but does not change peptide selectivity over different ligands.

Pro-Inflammatory and Anti-Inflammatory Interleukins in Infectious Diseases: A Comprehensive Review

“…IL-1α and IL-1β are pro-inflammatory and are produced during infection, tissue damage, or other inflammatory stimuli such as exposure to allergens, toxins, or stress. These cytokines act by binding to the IL-1 receptor (IL-1R), initiating a signaling pathway leading to the production of other inflammatory mediators and recruitment of immune cells to the infection or injury site [ 22 , 23 ]. IL-1Ra is a competitive inhibitor of IL-1α and IL-1β, preventing their binding to the IL-1R and dampening the inflammatory response.…”

Targeting peptide‐mediated interactions in omics

“…In this way, their disordered conformation was constrained into native ordered form (i.e., α-helix and Ω-loop) in free state, thus considerably promoting the peptide binding to TEAD by reducing indirect readout [75]. Since the hydrocarbon bridge and disulfide linker are generally designed to point out of the protein B-SIP complex interface, they generally have only a moderate effect on enthalpy in direct readout of the complex binding, but can substantially reduce entropy in indirect readout upon the binding [76].…”

“…In this way, their disordered conformation was constrained into native ordered form (i.e., α‐helix and Ω‐loop) in free state, thus considerably promoting the peptide binding to TEAD by reducing indirect readout [75]. Since the hydrocarbon bridge and disulfide linker are generally designed to point out of the protein B–SIP complex interface, they generally have only a moderate effect on enthalpy in direct readout of the complex binding, but can substantially reduce entropy in indirect readout upon the binding [76]. Consequently, the stapling/cyclization‐addressed entropic reduction can be roughly regarded as a constant, which only improves (absolute) SIP binding affinity towards protein B, but does not change (relative) SIP binding specificity over protein B and other proteins involved in the PMI [77].…”