The IKK-binding domain of NEMO is an irregular coiled coil with a dynamic binding interface

Sci Rep. 2019 Feb 27;9(1):2950. doi: 10.1038/s41598-019-39588-2.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Binding Sites / physiology
  • Cell Line
  • Crystallography, X-Ray
  • Escherichia coli / genetics
  • Humans
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism*
  • NF-kappa B / metabolism*
  • Protein Binding / physiology
  • Protein Domains
  • Signal Transduction / physiology


  • IKBKG protein, human
  • NF-kappa B
  • I-kappa B Kinase