The IKK-binding domain of NEMO is an irregular coiled coil with a dynamic binding interface
Year: 2019
Type: article
Abstract: NEMO is an essential component in the activation of the canonical NF-κB pathway and exerts its function by recruiting the IκB kinases (IKK) to the IKK complex. Inhibition of the NEMO/IKKs interaction is an attractive therapeutic paradigm for diseases related to NF-κB mis-regulation, but a difficult endeavor because of the extensive protein-protein interface. Here we report the high-resolution structure of the unbound IKKβ-binding domain of NEMO that will greatly facilitate the design of NEMO/IKK inhibitors. The structures of unbound NEMO show a closed conformation that partially occludes the three binding hot-spots and suggest a facile transition to an open state that can accommodate ligand binding. By fusing coiled-coil adaptors to the IKKβ-binding domain of NEMO, we succeeded in creating a protein with improved solution behavior, IKKβ-binding affinity and crystallization compatibility, which will enable the structural characterization of new NEMO/inhibitor complexes.
Source: Scientific Reports
Institution: Dartmouth College
Language: English
Topic: NF-κB Signaling Pathways
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $1,790
Awards: G1285306620, G1868695577, G241279073, G3262563802, G357145406, Targeting the IKK-binding Domain of NEMO for Inhibitors Discovery, G3850097093, G4298693369, G4972998915, G5417557083, G5493493709, G5633341255, G5765906131, G6733788163, G7431855654, G7463374569, G7466443226, Dissecting the Molecular Mechanisms of Selective Autophagy, The Institute for Biomolecular Targeting
OpenAlex ID: W2915155226