Modular interface of the IL-4 – IL-4 receptor interaction. (a) The interface between IL-4 and IL-4Rα consists of three clusters that contribute binding free energy independently of each other. Hydrogen bonding only occurs within one particular cluster but does not extend between two different clusters. Color coding represents the binding free energy that each residue contributes to the ligand-receptor interaction (red: ΔG = 3.5 kcal mol-1; orange: 3.5 kcal mol-1 > ΔG = 1.7 kcal mol-1; yellow: 1.6 kcal mol-1 > ΔG = 0.5 kcal mol-1; dark grey: 0.5 > ΔG > 0 kcal mol-1. (b) Cluster I is centred on Glu9 of IL-4, which is one of the two main binding determinants of the IL-4 – IL-4Rα interaction. (c) IL-4 Arg88 is the central residue in cluster II forming a bi-dentate saltbridge with IL-4Rα Asp72. (d) Cluster III consists of a hydrogen-bonding network comprising positively charged residues on the IL-4 interface (Arg81, Arg85) and negatively charged residues on the IL-4Rα epitope (Asp67, Asp125).