2yel

Crystal Structure of the First Bromodomain of Human Brd4 with the inhibitor GW841819X

spinqualitylabelsall models 2yel, resolution 1.65Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2yel is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: EDO, WSH Related: 2yem, 2yek 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 Epigenetic mechanisms of gene regulation have a profound role in normal development and disease processes. An integral part of this mechanism occurs through lysine acetylation of histone tails which are recognized by bromodomains. While the biological and structural characterization of many bromodomain containing proteins has advanced considerably, the therapeutic tractability of this protein family is only now becoming understood. This paper describes the discovery and molecular characterization of potent (nM) small molecule inhibitors that disrupt the function of the BET family of bromodomains (Brd2, Brd3, and Brd4). By using a combination of phenotypic screening, chemoproteomics, and biophysical studies, we have discovered that the protein-protein interactions between bromodomains and acetylated histones can be antagonized by selective small molecules that bind at the acetylated lysine recognition pocket. X-ray crystal structures of compounds bound into bromodomains of Brd2 and Brd4 elucidate the molecular interactions of binding and explain the precisely defined stereochemistry required for activity. Discovery and Characterization of Small Molecule Inhibitors of the BET Family Bromodomains.,Chung CW, Coste H, White JH, Mirguet O, Wilde J, Gosmini RL, Delves C, Magny SM, Woodward R, Hughes SA, Boursier EV, Flynn H, Bouillot AM, Bamborough P, Brusq JM, Gellibert FJ, Jones EJ, Riou AM, Homes P, Martin SL, Uings IJ, Toum J, Clement CA, Boullay AB, Grimley RL, Blandel FM, Prinjha RK, Lee K, Kirilovsky J, Nicodeme E J Med Chem. 2011 Jun 9;54(11):3827-3838. Epub 2011 May 13. PMID:21568322 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Bromodomain-containing protein 3D structures

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