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

Scientific Reports
Adam H BarczewskiMaria Pellegrini

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.

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Citations

Aug 28, 2020·Biochimica Et Biophysica Acta. Proteins and Proteomics·Myung Soo KoTom Huxford
May 9, 2021·Current Opinion in Structural Biology·Mohammad ElGamacy, Birte Hernandez Alvarez

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Methods Mentioned

BETA
ubiquitination
nuclear translocation
NMR
X-ray
size exclusion chromatography
circular dichroism

Software Mentioned

NEMO
MR
STARANISO
NAMD
SWISS
PairCoils2
R
CASTp
COOT
EEAA

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