4kv4 | pdb_00004kv4

Brd4 Bromodomain 2 in Complex with Acetylated Rel Peptide

spinqualitylabelsall models 4kv4, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4kv4 is a 2 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 2Å Ligands: ALY, DTT 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. Function BRD4_HUMAN Plays a role in a process governing chromosomal dynamics during mitosis (By similarity). Publication Abstract from PubMed Acetylation of the RelA subunit of NF-kappaB at lysine-310 regulates the transcriptional activation of NF-kappaB target genes and contributes to maintaining constitutively active NF-kappaB in tumors. Bromodomain-containing factor Brd4 has been shown to bind to acetylated lysine-310 (AcLys310) and to regulate the transcriptional activity of NF-kappaB, but the role of this binding in maintaining constitutively active NF-kappaB in tumors remains elusive. In this study, we demonstrate the structural basis for the binding of bromodomains (BDs) of bromodomain-containing protein 4 (Brd4) to AcLys310 and identify the BD inhibitor JQ1 as an effective small molecule to block this interaction. JQ1 suppresses TNF-alpha-mediated NF-kappaB activation and NF-kappaB-dependent target gene expression. In addition, JQ1 inhibits the proliferation and transformation potential of A549 lung cancer cells and suppresses the tumorigenicity of A549 cells in severe combined immunodeficiency mice. Furthermore, we demonstrate that depletion of Brd4 or treatment of cells with JQ1 induces the ubiquitination and degradation of the constitutively active nuclear form of RelA. Our results identify a novel function of Brd4 in maintaining the persistently active form of NF-kappaB found in tumors, and they suggest that interference with the interaction between acetylated RelA and Brd4 could be a potential therapeutic approach for the treatment of NF-kappaB-driven cancer.Oncogene advance online publication, 20 May 2013; doi:10.1038/onc.2013.179. Brd4 maintains constitutively active NF-kappaB in cancer cells by binding to acetylated RelA.,Zou Z, Huang B, Wu X, Zhang H, Qi J, Bradner J, Nair S, Chen LF Oncogene. 2013 May 20. doi: 10.1038/onc.2013.179. PMID:23686307 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Bromodomain-containing protein 3D structures

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