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Configurational Differences and Binding Mechanisms of Interleukin-1 Receptor-Associated Kinase 1

Interleukin-l receptor-associated kinase 1 (IRAKI) is crucial for downstream regulation of the toll-like receptor signaling pathway and is involved in innate immune system, inflammatory diseases, and cancers. There is an urgent need for developing inhibitors that target IRAKI. To address this issue, we have developed a method to explore the structural dynamics of IRAKI by utilizing the abundant structures of IRAK4. Our results show that IRAKI should have four configuration types, including Type-CL (left of C-lobe), Type-CR (right of C-lobe), Type-A (ATP site), and Type-N (N-lobe), according to the ligand occupancy consistency among the four groups of 45 IRAK4 ligand complexes. Each type demonstrates a distinct binding environment between IRAKI and the bound ligands for guiding the specific inhibitor design. We evaluated our prediction models for each type and discovered a new Type-N inhibitor, ponatinib, which is 100 times more potent for IRAKI (93nM) than for IRAK4 (>10$\mu$M), based on our kinase inhibition assay. To the best of our knowledge, we are the first team to propose a novel method to study the configurational flexibility and Type-N inhibitors of IRAKI. We believe that our approach provides a useful strategy for designing selective inhibitors for a specific kinase family.