Crystal structure of human IRAK1

Innate immune signaling has an essential role in inflammation, and dysfunction of signaling components in these pathways contributes to autoimmunity and cancer. Interleukin-1 receptor-associated kinase (IRAK) family members are key mediators of signal transduction by Toll-like receptors and Interleukin-1 receptors in innate immunity and therefore serve as potential therapeutic targets for these diseases. The crystal structure of the IRAK1 kinase domain in complex with a small molecule inhibitor reveals important structural details of the kinase that provide insights into the design of selective IRAK inhibitors. Characterization of IRAK1 heterodimerization with the upstream kinase IRAK4 suggests a mechanism of IRAK1 activation by IRAK4.