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

Yun Ti Chen, Cheng Hsuan Wu, Yi Cyun Chen, Yen Chao Hsu, Yu Wei Huang, Jinn Moon Yang

研究成果: Conference contribution同行評審

摘要

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\muM), 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.

原文English
主出版物標題Proceedings - IEEE 20th International Conference on Bioinformatics and Bioengineering, BIBE 2020
發行者Institute of Electrical and Electronics Engineers Inc.
頁面160-167
頁數8
ISBN(電子)9781728195742
DOIs
出版狀態Published - 十月 2020
事件20th IEEE International Conference on Bioinformatics and Bioengineering, BIBE 2020 - Virtual, Cincinnati, United States
持續時間: 26 十月 202028 十月 2020

出版系列

名字Proceedings - IEEE 20th International Conference on Bioinformatics and Bioengineering, BIBE 2020

Conference

Conference20th IEEE International Conference on Bioinformatics and Bioengineering, BIBE 2020
國家United States
城市Virtual, Cincinnati
期間26/10/2028/10/20

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