Molecular Basis for Shared Cytokine Recognition Revealed in the Structure of an Unusually High Affinity Complex between IL-13 and IL-13Rα2

SummaryInterleukin-13 is a cytokine important for development of T helper cell type 2 (Th2) responses and plays a critical role in asthma and allergy. The IL-13 Receptor α2 (IL-13Rα2) is a receptor for IL-13 lacking canonical Jak/STAT signaling functions. Here we present the crystal structure along with a mutational and biophysical analysis of the IL-13/IL-13Rα2 complex. While retaining a similar mode of IL-13 binding to its related signaling receptor, IL-13Rα1, IL-13Rα2 uses peripheral receptor residues unused in the IL-13/IL-13Rα1 complex to generate a larger and more complementary interface for IL-13. This results in a four orders of magnitude increase in affinity, to the femtomolar level, compared to IL-13Rα1. Alanine scanning mutagenesis of the IL-13 interface reveals several common “hotspot” residues important for binding to both receptors, but also identifies a prominent IL-13Rα2-specific contact. These results provide a framework for development of receptor subtype-selective IL-13 antagonists and indicate a decoy function for IL-13Rα2.

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► The crystal structure of the IL-13/IL-13Rα2 complex was solved at 3.1 Å resolution
► The complex affinity is <100 fM, among the tightest ligand-receptor interactions known
► IL-13Rα2 expands on a common binding site with its signaling paralogue, IL-13Rα1
► An Ala scan defined a “hotspot” on IL-13 important for interaction with both receptors