Nuclear factor NF-kappa-B p65 subunit–CREB-binding protein interface (NF-κB p65–CBP PPI)

The NF-κB p65–CBP protein–protein interface is a critical regulatory node in the canonical NF-κB signaling pathway, facilitating the physical interaction between the transactivation domain (TAD) of the p65 (RelA) subunit and the CREB-binding protein (CBP) coactivator. This interaction, often triggered by the phosphorylation of p65 at Ser276, is essential for the recruitment of CBP to NF-κB target gene promoters, where it acts as a histone acetyltransferase to promote the transcription of pro-inflammatory and pro-survival genes. Dysregulation of this interface is strongly linked to the pathogenesis of various cancers and chronic inflammatory diseases, such as rheumatoid arthritis and asthma. Targeting this specific protein-protein interaction offers a more selective therapeutic strategy than global NF-κB inhibition, potentially minimizing the toxicity associated with broad immune suppression. Several experimental small molecules and natural products, including triptolide and KIX-domain inhibitors like KG-501, have demonstrated the ability to disrupt this interface and attenuate NF-κB-driven disease processes.

Other names

p65-CBP interactionRelA-CBP interactionp65-CREBBP interactionp65-CBP complexNF-κB p65–CBP protein–protein interface

Inhibition of the protein-protein interaction between the p65 transactivation domain (TAD) and the CBP coactivator domains (specifically KIX or TAZ1), thereby preventing the recruitment of CBP to NF-κB target gene promoters and reducing p65 acetylation and transcriptional activity.