Molecular modeling and rational design of disulfide-stapled self-inhibitory peptides to target IL-17A/IL-17RA interaction

J Mol Recognit. 2023 Aug;36(8):e3045. doi: 10.1002/jmr.3045. Epub 2023 Jul 6.

Abstract

Interleukin-17A (IL-17A) is a pro-inflammatory cytokine implicated in diverse autoimmune and inflammatory disorders such as psoriasis and Kawasaki disease. Mature IL-17A is a homodimer that binds to the extracellular type-III fibronectin D1:D2-dual domain of its cognate IL-17 receptor A (IL-17RA). In this study, we systematically examined the structural basis, thermodynamics property, and dynamics behavior of IL-17RA/IL-17A interaction and computationally identified two continuous hotspot regions separately from different monomers of IL-17A homodimer that contribute significantly to the interaction, namely I-shaped and U-shaped segments, thus rendered as a peptide-mediated protein-protein interaction (PmPPI). Self-inhibitory peptides (SIPs) are derived from the two segments to disrupt IL-17RA/IL-17A interaction by competitively rebinding to the IL-17A-binding pocket on IL-17RA surface, which, however, only have a weak affinity and low specificity for IL-17RA due to lack of the context support of intact IL-17A protein, thus exhibiting a large flexibility and intrinsic disorder when splitting from the protein context and incurring a considerable entropy penalty when rebinding to IL-17RA. The U-shaped segment is further extended, mutated and stapled by a disulfide bridge across its two strands to obtain a number of double-stranded cyclic SIPs, which are partially ordered and conformationally similar to their native status at IL-17RA/IL-17A complex interface. Experimental fluorescence polarization assays substantiate that the stapling can moderately or considerably improve the binding affinity of U-shaped segment-derived peptides by 2-5-fold. In addition, computational structural modeling also reveals that the stapled peptides can bind in a similar mode with the native crystal conformation of U-shaped segment in IL-17RA pocket, where the disulfide bridge is out of the pocket for avoiding intervene of the peptide binding.

Keywords: Kawasaki disease; disulfide stapling; interleukin-17 receptor A; interleukin-17A; peptide-mediated interaction; self-inhibitory peptide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Interleukin-17* / chemistry
  • Interleukin-17* / metabolism
  • Interleukin-17* / pharmacology
  • Models, Molecular
  • Peptides / chemistry
  • Protein Binding
  • Receptors, Interleukin-17* / chemistry
  • Receptors, Interleukin-17* / metabolism

Substances

  • Interleukin-17
  • Receptors, Interleukin-17
  • Peptides