Model of ligand/receptor complex formation by the IL-1-like cytokines IL-18 and IL-1F7 with IL-18RRα and with the accessory protein IL-18RRβ.

IL-18 is an immunomodulatory/inflammatory protein belonging to the IL-1 family of innate cytokines. IL-18 activates target cells following interaction with IL-18RRα, an Ig-like protein belonging to the IL-1R family. As for IL-11β, after interaction of IL-18 with IL-18RRα, a second accessory receptor chain (IL-18RRβ, another member of the IL-1R family) is recruited to the complex and allows signal transduction. The complex of IL-11β with its receptor IL-1RI has been crystallised and its structure resolved. A subsequent modelling study has allowed to describe the interaction of the accessory chain IL-1RAcP with the IL-11β/IL-1RI complex. Nothing is known about the interaction between IL-18, IL-18RRα, and IL-18RRβ. In this study, the interaction of IL-18 with IL-18RRα and the subsequent interaction of the complex with IL-18RRβ has been studied in silico by molecular modelling, on the basis of the structural data of the IL-11β/IL-1RI/IL-1RAcP complex. First, IL-18RRα and IL-18RRβ have been modelled on the crystal structure of IL-1RI, PDB code 1ITB. The alignment was generated with ClustalW, the 3D structure prediction was made with MODELLER9 and validated with PROSA/PROCHECK. Then, the IL-18 NMR structure (PDB code 1J0S) has been docked to IL-18RRα using AutoDock 3.05 on the basis of mutagenesis data. At last, IL-18RRβ has been docked to the predicted IL-18/IL-18RRα model. Another IL-1-like molecule, IL-1F7, can bind to IL-18RRα, but allegedly does not recruit IL-18RRβ into an activating complex. Modelling and docking of IL-1F7 to the IL-18RRα model and subsequent docking of the IL-18RRβ model to the modelled IL-1F7/IL-18RRα complex is in progress