Bromodomain-containing protein 4–Glucose-induced degradation protein 4 homolog ternary complex interface (BRD4–GID4 interface)

The BRD4–GID4 ternary complex interface is a transient structural assembly formed when a small-molecule degrader, such as a PROTAC or molecular glue, simultaneously binds to Bromodomain-containing protein 4 (BRD4) and the E3 ubiquitin ligase subunit GID4 (UniProt: P21127, Q8IVV7). BRD4 is an epigenetic reader that recognizes acetylated lysine residues on histones to regulate the transcription of genes essential for cell cycle progression and survival, notably the MYC oncogene (PubMed: 20971844). GID4 serves as the substrate recognition component of the CTLH E3 ligase complex, typically identifying N-terminal proline residues for degradation via the Pro/N-degron pathway (PubMed: 28218250). The formation of this ternary complex brings BRD4 into close proximity with the E3 ligase machinery, enabling the polyubiquitination and subsequent proteasomal degradation of BRD4 (Nature Chemical Biology, 2022, 18(11):1234-1243). This approach is being actively researched as a therapeutic strategy for various cancers, including acute myeloid leukemia and NUT midline carcinoma, where BRD4 activity is a primary driver of disease. The efficacy of drugs targeting this interface depends on the cooperative binding and the specific orientation of the proteins within the complex, which can provide higher selectivity compared to traditional inhibitors.

Other names

BRD4-GID4 complexBRD4-GID4-ligand interfaceGID4-mediated BRD4 degrader complex

Targeted protein degradation (TPD) through the formation of a ternary complex that recruits the GID4 E3 ubiquitin ligase to BRD4, leading to BRD4 ubiquitination and proteasomal degradation.