NF-kappa-B is sequestered in the cytosol of unstimulated cells through the interactions with a class of inhibitor proteins, called NF-kappa-B inhibitors (IkBs, NFKBIA and NFKBIB). IkBs proteins such as NFKBIA or NFKBIB are characterized by the presence of six to seven ankyrin repeat motifs, which mediate interaction with the Rel homology domain (RHD). RHD mediates DNA binding, dimerization and nuclear localization (Jacobs MD & Harrison SC 1998; Manavalan B et al. 2010). NF-kappa-B inhibitors (IkBs) mask the nuclear localization signal (NLS) of NFKB preventing its nuclear translocation (Jacobs MD & Harrison SC 1998; Cervantes CF et al. 2011). A key event in NF-kappa-B activation involves phosphorylation of IkB (at sites equivalent to Ser32 and Ser36 of NFKBIA (IkB-alpha) or Ser19 and Ser22 of NFKBIB (IkB-beta) by the IκB kinase (IKK) complex. The phosphorylated NFKBIA is recognized by the E3 ligase complex and targeted for ubiquitin-mediated proteasomal degradation, releasing the NF-kappa-B dimer p50/p65 into the nucleus to turn on target genes (Karin M & Ben-Neriah Y 2000, Kanarek N & Ben-Neriah Y 2012; Hoffmann A et al. 2006). Crystal structures of NF-kappa-B inhibitors:NF-kappaB complexes revealed that an NF-kappa-B dimer binds to one IkB molecule (Jacobs MD & Harrison SC 1998; Ghosh G et 2012).