IL-1 ailesinin yapısal yönlerinin moleküler dinamik simülasyonu kullanılarak araştırılması

Interleukin-1 (IL-1) is a master mediator of innate immunity and inflammation. There is a tight regulation by receptor antagonists, decoy and soluble receptors both extracellular and intracellular levels. Members of the IL-1 Receptor family include type I IL-1 receptor (IL-1RI), IL-1 receptor-like 1 (IL-1RPL1, also called as ST2) and IL-18 receptor as primary receptors, type II IL-1 (IL-1RII) receptor as a decoy receptor, IL-1 receptor accessory protein (IL-1RAcP) as a secondary receptor. One of the IL-1 family receptor ligands, IL-1β, has a major role in immune responses. It signals through binding its primary receptor IL-1RI and its secondary receptor IL- 1RAcP. IL-1 has also a naturally occurring antagonist functions via binding to IL-1RI. Therefore, targeting IL-1R is a common therapeutic strategy for autoinflammatory diseases. However, structural basis of IL-1 antagonism is still unknown. Here we used classical molecular dynamics to reveal key aspects of the signalling complex of IL-1β and interaction between its primary and secondary receptors. We showed that high D3 domain fluctuation of IL-1RI when it is bound to antagonist can have an important role in inhibiting IL-1 signalling. In addition to IL-1 complexes, we have performed classical molecular dynamics simulations of single soluble forms of IL-1 receptors. We have found that in the absence of ligand, IL-1RI, ST2 and IL-18R1 take conformations that are dramatically different from their complex conformations. There are also experimental studies which support our findings on these different conformations. One of them is from a x-ray structure in which close form of IL- 1RI is in complex with a short peptide. In addition, SAXS studies confirm that ligand-free ST2 has different conformers in solution. These different conformers cannot participate in ligand binding; therefore, this can be a new finding on inhibitory mechanism of IL-1 superfamily.