TANK-binding kinase 1 (TBK1)–Inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKKε) complex interface (TBK1–IKKε interface)

The TANK-binding kinase 1 (TBK1) and Inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKKε) complex interface is a vital regulatory site in the innate immune signaling network (UniProt Q9UHD2, Q14164). These non-canonical IKK kinases share significant structural homology and are responsible for phosphorylating interferon regulatory factors (IRF3/7) to induce Type I interferon production (PubMed: 23023374). The interface facilitates the assembly of these kinases with various adaptor proteins, such as TANK, NAP1, and SINTBAD, which are necessary for their activation and subcellular localization (PubMed: 22343619). In the context of disease, the TBK1–IKKε complex is often overexpressed or hyperactivated in several cancers, including breast and lung cancer, where it supports tumor cell survival and immune evasion (PubMed: 30635424). It also plays a role in neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS) and autoimmune conditions like Systemic Lupus Erythematosus (SLE) (PubMed: 26030324). While most pharmacological agents currently target the ATP-binding site of the kinase domain, the complex interface is an emerging target for protein-protein interaction (PPI) inhibitors. Targeting this interface aims to selectively block specific signaling branches, potentially offering a more refined therapeutic window than global kinase inhibition. Research into stapled peptides and small-molecule disruptors of this interface is ongoing to address the limitations of current kinase inhibitors (PubMed: 28219902).

Other names

TBK1-IKBKE interfaceNon-canonical IKK complex interfaceTBK1-IKKε dimerization siteTBK1-IKKε-adaptor complex

Inhibition of kinase activity or disruption of protein-protein interactions within the signaling complex.