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8wyp

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High Resolution Crystal Structure of Brd4 BD-1 in Complex with a Novel Inhibitor Precursor

Structural highlights

8wyp is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.24Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

BRD4_HUMAN Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein.^[1] ^[2]

Function

BRD4_HUMAN Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).

Publication Abstract from PubMed

The inhibition of BRD4 bromodomain is an effective therapeutic strategy for a variety of diseases in which BRD4 are implicated. Herein, we identified a small-molecule BRD4 inhibitor hit named compound 3 using high-throughput screening. The 1.6 A resolution co-crystal structure confirmed that the compound occupies the KAc recognition pockets of BRD4 by forming key hydrogen bonds with Asn140 and engaging in hydrophobic interactions, thus impedes the binding of acetylated lysine to BRD4. These findings suggest compound 3 can be a lead compound to develop a structurally novel BRD4 inhibitors.

High resolution crystal structure of BRD4-BD1 in complex with a novel inhibitor precursor.,Ma X, Wang M, Wang F, Li J, Zhang Z, Zhu J, Liu B Biochem Biophys Res Commun. 2024 Jan 1;690:149284. doi: , 10.1016/j.bbrc.2023.149284. Epub 2023 Nov 20. PMID:38006801^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ French CA, Miyoshi I, Kubonishi I, Grier HE, Perez-Atayde AR, Fletcher JA. BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma. Cancer Res. 2003 Jan 15;63(2):304-7. PMID:12543779
↑ French CA, Miyoshi I, Aster JC, Kubonishi I, Kroll TG, Dal Cin P, Vargas SO, Perez-Atayde AR, Fletcher JA. BRD4 bromodomain gene rearrangement in aggressive carcinoma with translocation t(15;19). Am J Pathol. 2001 Dec;159(6):1987-92. PMID:11733348 doi:10.1016/S0002-9440(10)63049-0
↑ Ma X, Wang M, Wang F, Li J, Zhang Z, Zhu J, Liu B. High resolution crystal structure of BRD4-BD1 in complex with a novel inhibitor precursor. Biochem Biophys Res Commun. 2024 Jan 1;690:149284. PMID:38006801 doi:10.1016/j.bbrc.2023.149284