The interleukin-2 and interleukin-4 receptors studied by molecular modelling.

Interleukin-2 (IL2) and interleukin-4 (IL4) are members of the four-helix bundle family of cytokines, whose receptors show similarity to each other and to the growth hormone receptor fold. These proteins help to control, among other things, the rate of clonal expansion of lymphocytes, and thus play an important role in the regulation of the immune system. They are therefore of interest as transmembrane signalling proteins, as well as potential pharmaceutical targets. We have modelled structures of the extracellular components of the IL2 and IL4 receptors based on the structure of the complex of human growth hormone with its receptor, and incorporating the recently discovered shared gamma c chain. The models provide possible explanations for several experimental observations, including those from site-directed mutagenesis around the binding sites. Receptor residues that may be close to important side chains on IL2 and IL4 are identified and possible effects of their mutation are discussed. A comparison is made between the models and the growth hormone complex, and between the gamma c chain bound to IL2 and to IL4. The models offer structural explanations for observed behaviour such as the effects of mutation of the A- and D-helices of the cytokines. In addition, they may be of use in the identification of residues which may interact in the ligand-receptor interfaces, and which would therefore be worthy of further investigation.