5kj0
From Proteopedia
CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH DB-1-264-2
Structural highlights
DiseaseBRD4_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] FunctionBRD4_HUMAN Plays a role in a process governing chromosomal dynamics during mitosis (By similarity). Publication Abstract from PubMedEvaluating the engagement of a small molecule ligand with a protein target in cells provides useful information for chemical probe optimization and pharmaceutical development. While several techniques exist that can be performed in a low-throughput manner, systematic evaluation of large compound libraries remains a challenge. In-cell engagement measurements are especially useful when evaluating compound classes suspected to target multiple cellular factors. In this study we used a bioluminescent resonant energy transfer assay to assess bromodomain engagement by a compound series containing bromodomain- and kinase-biasing polypharmacophores based on the known dual BRD4 bromodomain/PLK1 kinase inhibitor BI2536. With this assay, we discovered several novel agents with bromodomain-selective specificity profiles and cellular activity. Thus, this platform aids in distinguishing molecules whose cellular activity is difficult to assess due to polypharmacologic effects. Assessment of Bromodomain Target Engagement by a Series of BI2536 Analogues with Miniaturized BET-BRET.,Koblan LW, Buckley DL, Ott CJ, Fitzgerald ME, Ember SW, Zhu JY, Liu S, Roberts JM, Remillard D, Vittori S, Zhang W, Schonbrunn E, Bradner JE ChemMedChem. 2016 Dec 6;11(23):2575-2581. doi: 10.1002/cmdc.201600502. Epub 2016 , Nov 15. PMID:27862999[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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