Abstract
The interleukin-1 receptor (IL-1R) is the founding member of the interleukin 1 receptor family which activates innate immune response by its binding to cytokines. Reports showed dysregulation of cytokine production leads to aberrant immune cells activation which contributes to auto-inflammatory disorders and diseases. Current therapeutic strategies focus on utilizing antibodies or chimeric cytokine biologics. The large protein-protein interaction interface between cytokine receptor and cytokine poses a challenge in identifying binding sites for small molecule inhibitor development. Based on the significant conformational change of IL-1R type 1 (IL-1R1) ectodomain upon binding to different ligands observed in crystal structures, we hypothesized that transient small molecule binding sites may exist when IL-1R1 undergoes conformational transition and thus suitable for inhibitor development. Here, we employed accelerated molecular dynamics (MD) simulation to efficiently sample conformational space of IL-1R1 ectodomain. Representative IL-1R1 ectodomain conformations determined from the hierarchy cluster analysis were analyzed by the SiteMap program which leads to identify small molecule binding sites at the protein-protein interaction interface and allosteric modulator locations. The cosolvent mapping analysis using phenol as the probe molecule further confirms the allosteric modulator site as a binding hotspot. Eight highest ranked fragment molecules identified from in silico screening at the modulator site were evaluated by MD simulations. Four of them restricted the IL-1R1 dynamical motion to inactive conformational space. The strategy from this study, subject to in vitro experimental validation, can be useful to identify small molecule compounds targeting the allosteric modulator sites of IL-1R and prevent IL-1R from binding to cytokine by trapping IL-1R in inactive conformations.
Highlights
The interleukin-1 (IL-1) family of ligands and receptors are important regulators of innate inflammatory and immune responses[1]
The results showed that IL-1R type 1 (IL-1R1) conformations obtained from four ligands (L951, L1882, L1192, L537) exhibiting smaller average rootmean-square deviations (RMSD) values were projected to much localized regions in the PC1/PC2 and PC1/PC3 subspaces
We hypothesized the existence of transient small molecule binding sites among multiple conformational states accessed by IL-1R1 which may be suitable for inhibitor development
Summary
The interleukin-1 (IL-1) family of ligands and receptors are important regulators of innate inflammatory and immune responses[1]. Eleven IL-1 ligands (or cytokines) and receptors were identified respectively [2] These IL-1 ligands function as agonists and antagonists to IL-1 signaling by binding to IL-1 receptors including ten single pass transmembrane proteins and IL-18BP which lacks transmembrane domain[3]. Regulation of inflammatory signaling via IL-1 family of receptors can be mediated either by its binding to the activating cytokines or antagonistic ligands such as IL-1Ra which inhibit downstream signaling [4]. SIL-1R1 and sST2 have only the ectodomain of their respective receptors, IL-1R1 and ST2 They circulate in the extracellular milieu to modulate their respective binding cytokines concentrations and attenuate the inflammatory responses mediated by these ligands [5,7,8]
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