6swn

N-TERMINAL BROMODOMAIN OF HUMAN BRD4 WITH iBET-BD1 (GSK778)

spinqualitylabelsall models 6swn, resolution 1.28Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6swn 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, GLU, LWB Gene: BRD4, HUNK1 (HUMAN) 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 The two tandem bromodomains of the BET proteins enable chromatin binding to facilitate transcription. Drugs that inhibit both bromodomains equally have shown efficacy in certain malignant and inflammatory conditions. To explore the individual functional contributions of the first (BD1) and second (BD2) bromodomains in biology and therapy, we developed selective BD1 and BD2 inhibitors. We found that steady-state gene expression primarily requires BD1 whereas the rapid increase of gene expression induced by inflammatory stimuli requires both BD1 and BD2 of all BET proteins. BD1 inhibitors phenocopied the effects of pan-BET inhibitors in cancer models whereas BD2 inhibitors were predominantly effective in models of inflammatory and autoimmune disease. These insights into the differential requirement of BD1 and BD2 for the maintenance and induction of gene expression may guide future BET targeted therapies. Selective targeting of BD1 and BD2 of the BET proteins in cancer and immuno-inflammation.,Gilan O, Rioja I, Knezevic K, Bell MJ, Yeung MM, Harker NR, Lam EYN, Chung CW, Bamborough P, Petretich M, Urh M, Atkinson SJ, Bassil AK, Roberts EJ, Vassiliadis D, Burr ML, Preston AGS, Wellaway C, Werner T, Gray JR, Michon AM, Gobbetti T, Kumar V, Soden PE, Haynes A, Vappiani J, Tough DF, Taylor S, Dawson SJ, Bantscheff M, Lindon M, Drewes G, Demont EH, Daniels DL, Grandi P, Prinjha RK, Dawson MA Science. 2020 Mar 19. pii: science.aaz8455. doi: 10.1126/science.aaz8455. PMID:32193360 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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