Histone acetyltransferase p300 (EP300) KIX domain (p300 KIX)

The p300 KIX domain is a structural motif within the Histone acetyltransferase p300 (EP300) that functions as a versatile scaffold for the assembly of transcriptional complexes (UniProt P45974). It mediates interactions with a diverse array of transactivation domains from transcription factors such as CREB, c-Myb, and MLL, thereby integrating multiple signaling pathways at the level of gene promoters (PMID: 12192000). This domain is essential for the regulation of genes involved in cell proliferation, differentiation, and hematopoiesis. Dysregulation of p300 KIX-mediated interactions is frequently implicated in the pathogenesis of various cancers, including acute myeloid leukemia and prostate cancer, where it promotes the expression of oncogenic drivers (PMID: 29150604). As a result, the p300 KIX domain is a target of intense drug discovery efforts aimed at developing small-molecule inhibitors that can selectively block these protein-protein interactions (PMID: 25514049). Such inhibitors offer a potential therapeutic strategy to reprogram gene expression in malignant cells. The domain's unique fold, consisting of three alpha-helices, provides two distinct binding sites for different transcription factors, allowing for complex regulatory control.

Other names

EP300 KIX domainp300 kinase-inducible domain interacting domainp300 KIX

The mechanism involves the competitive inhibition of protein-protein interactions (PPIs) between the KIX domain and the transactivation domains of transcription factors such as CREB and c-Myb, thereby preventing the recruitment of p300 to target gene promoters and inhibiting oncogenic transcription (PMID: 12192000, PMID: 25514049, PMID: 29150604).