6mi4

Publication Abstract from PubMed

NEMO is an essential component in the activation of the canonical NF-kappaB pathway and exerts its function by recruiting the IkappaB kinases (IKK) to the IKK complex. Inhibition of the NEMO/IKKs interaction is an attractive therapeutic paradigm for diseases related to NF-kappaB mis-regulation, but a difficult endeavor because of the extensive protein-protein interface. Here we report the high-resolution structure of the unbound IKKbeta-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 IKKbeta-binding domain of NEMO, we succeeded in creating a protein with improved solution behavior, IKKbeta-binding affinity and crystallization compatibility, which will enable the structural characterization of new NEMO/inhibitor complexes.

The IKK-binding domain of NEMO is an irregular coiled coil with a dynamic binding interface.,Barczewski AH, Ragusa MJ, Mierke DF, Pellegrini M Sci Rep. 2019 Feb 27;9(1):2950. doi: 10.1038/s41598-019-39588-2. PMID:30814588^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.