6egd › Citations

Conformational flexibility and inhibitor binding to unphosphorylated interleukin-1 receptor-associated kinase 4 (IRAK4).

Wang L, Ferrao R, Li Q, Hatcher JM, Choi HG, Buhrlage SJ, Gray NS, Wu H
J Biol Chem 294 4511-4519 (2019)
Related entries: 6eg9, 6ega, 6ege, 6egf

Cited: 10 times
EuropePMC logo PMID: 30679311

Abstract

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a key player in innate immune and inflammatory responses, performing a critical role in signal transduction downstream of Toll-like receptors and interleukin-1 (IL-1) receptors. Upon ligand binding and via its N-terminal death domain, IRAK4 is recruited to an oligomeric receptor that is proximal to the Myddosome signaling complex, inducing IRAK4 kinase domain dimerization, autophosphorylation, and activation. To date, all known IRAK4 structures are in the active conformation, precluding a good understanding of IRAK4's conformational dynamics. To address this issue, here we first solved three crystal structures of the IRAK4 kinase domain (at ≤2.6 Å resolution), in its unphosphorylated, inactive state bound to either the ATP analog AMP-PNP or to one of the two small-molecule inhibitors JH-I-25 and JH-I-17. The structures disclosed that although the structure in complex with AMP-PNP is in an "αC-out" inactive conformation, those in complex with type I inhibitors assume an active "Asp-Phe-Gly (DFG)-in" and "αC-in" conformation. The ability of unphosphorylated IRAK4 to take on variable conformations prompted us to screen for small-molecule inhibitors that bind preferentially to unphosphorylated IRAK4, leading to the identification of ponatinib and HG-12-6. Solving the structures of unphosphorylated IRAK4 in complex with these two inhibitors, we found that they both bind as type II inhibitors with IRAK4 in a "DFG-out" conformation. Collectively, these structures reveal conformational flexibility of unphosphorylated IRAK4 and provide unexpected insights into the potential use of small molecules to modulate IRAK4 activity in cancer, autoimmunity, and inflammation.

Articles - 6egd mentioned but not cited (1)

  1. Conformational flexibility and inhibitor binding to unphosphorylated interleukin-1 receptor-associated kinase 4 (IRAK4). Wang L, Ferrao R, Li Q, Hatcher JM, Choi HG, Buhrlage SJ, Gray NS, Wu H. J Biol Chem 294 4511-4519 (2019)


Reviews citing this publication (1)

  1. Tolerogenic dendritic cells and TLR4/IRAK4/NF-κB signaling pathway in allergic rhinitis. Kang C, Li X, Liu P, Liu Y, Niu Y, Zeng X, Zhao H, Liu J, Qiu S. Front Immunol 14 1276512 (2023)

Articles citing this publication (8)

  1. Kincore: a web resource for structural classification of protein kinases and their inhibitors. Modi V, Dunbrack RL. Nucleic Acids Res 50 D654-D664 (2022)
  2. Dimeric Structure of the Pseudokinase IRAK3 Suggests an Allosteric Mechanism for Negative Regulation. Lange SM, Nelen MI, Cohen P, Kulathu Y. Structure 29 238-251.e4 (2021)
  3. Structural analysis of receptor-like kinase SOBIR1 reveals mechanisms that regulate its phosphorylation-dependent activation. Wei X, Wang Y, Zhang S, Gu T, Steinmetz G, Yu H, Guo G, Liu X, Fan S, Wang F, Gu Y, Xin F. Plant Commun 3 100301 (2022)
  4. Analysis of the ERK Pathway Cysteinome for Targeted Covalent Inhibition of RAF and MEK Kinases. Romany A, Liu R, Zhan S, Clayton J, Shen J. J Chem Inf Model 63 2483-2494 (2023)
  5. Network Pharmacology- and Molecular Docking-Based Identification of Potential Phytocompounds from Argyreia capitiformis in the Treatment of Inflammation. Obaidullah AJ, Alanazi MM, Alsaif NA, Alanazi AS, Albassam H, Az A, Alwassil OI, Alqahtani AM, Tareq AM. Evid Based Complement Alternat Med 2022 8037488 (2022)
  6. Structural and biochemical basis of Arabidopsis FERONIA receptor kinase-mediated early signaling initiation. Kong Y, Chen J, Jiang L, Chen H, Shen Y, Wang L, Yan Y, Zhou H, Zheng H, Yu F, Ming Z. Plant Commun 4 100559 (2023)
  7. Discovery of IRAK4 Inhibitors BAY1834845 (Zabedosertib) and BAY1830839. Bothe U, Günther J, Nubbemeyer R, Siebeneicher H, Ring S, Bömer U, Peters M, Rausch A, Denner K, Himmel H, Sutter A, Terebesi I, Lange M, Wengner AM, Guimond N, Thaler T, Platzek J, Eberspächer U, Schäfer M, Steuber H, Zollner TM, Steinmeyer A, Schmidt N. J Med Chem 67 1225-1242 (2024)
  8. Unraveling Extremely Damaging IRAK4 Variants and Their Potential Implications for IRAK4 Inhibitor Efficacy. Behairy MY, Eid RA, Otifi HM, Mohammed HM, Alshehri MA, Asiri A, Aldehri M, Zaki MSA, Darwish KM, Elhady SS, El-Shaer NH, Eldeen MA. J Pers Med 13 1648 (2023)


Quick links