NF-κB plays a vital role in cellular immune and inflammatory response, survival, 
and proliferation by regulating the transcription of various genes involved in 
these processes. To activate transcription, RelA (a prominent NF-κB family 
member) interacts with transcriptional co-activators like CREB-binding protein 
(CBP) and its paralog p300 in addition to its cognate κB sites on the 
promoter/enhancer regions of DNA. The RelA:CBP/p300 complex is comprised of two 
components--first, DNA binding domain of RelA interacts with the KIX domain of 
CBP/p300, and second, the transcriptional activation domain (TAD) of RelA binds 
to the TAZ1 domain of CBP/p300. A phosphorylation event of a well-conserved 
RelA(Ser276) is prerequisite for the former interaction to occur and is 
considered a decisive factor for the overall RelA:CBP/p300 interaction. The role 
of the latter interaction in the transcription of RelA-activated genes remains 
unclear. Here we provide the solution structure of the latter component of the 
RelA:CBP complex by NMR spectroscopy. The structure reveals the folding of 
RelA-TA2 (a section of TAD) upon binding to TAZ1 through its well-conserved 
hydrophobic sites in a series of grooves on the TAZ1 surface. The structural 
analysis coupled with the mechanistic studies by mutational and isothermal 
calorimetric analyses allowed the design of RelA-mutants that selectively 
abrogated the two distinct components of the RelA:CBP/p300 interaction. Detailed 
studies of these RelA mutants using cell-based techniques, mathematical 
modeling, and genome-wide gene expression analysis showed that a major set of 
the RelA-activated genes, larger than previously believed, is affected by this 
interaction. We further show how the RelA:CBP/p300 interaction controls the 
nuclear response of NF-κB through the negative feedback loop of NF-κB pathway. 
Additionally, chromatin analyses of RelA target gene promoters showed 
constitutive recruitment of CBP/p300, thus indicating a possible role of 
CBP/p300 in recruitment of RelA to its target promoter sites.