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{{STRUCTURE_4o7b|  PDB=4o7b  |  SCENE=  }}
==Crystal structure of the first bromodomain of human BRD4 in complex with SB-284847-BT==
===Crystal structure of the first bromodomain of human BRD4 in complex with SB-284847-BT===
<StructureSection load='4o7b' size='340' side='right' caption='[[4o7b]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
{{ABSTRACT_PUBMED_24568369}}
== Structural highlights ==
 
<table><tr><td colspan='2'>[[4o7b]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4O7B OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4O7B FirstGlance]. <br>
==Disease==
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2RJ:2-(2,3-DIMETHYLPHENOXY)-4-[4-(4-FLUOROPHENYL)-1-(PIPERIDIN-4-YL)-1H-IMIDAZOL-5-YL]PYRIMIDINE'>2RJ</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene><br>
<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4o70|4o70]], [[4o71|4o71]], [[4o72|4o72]], [[4o73|4o73]], [[4o74|4o74]], [[4o75|4o75]], [[4o76|4o76]], [[4o77|4o77]], [[4o78|4o78]], [[4o7a|4o7a]], [[4o7c|4o7c]], [[4o7e|4o7e]], [[4o7f|4o7f]]</td></tr>
<tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BRD4, HUNK1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4o7b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4o7b OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4o7b RCSB], [http://www.ebi.ac.uk/pdbsum/4o7b PDBsum]</span></td></tr>
<table>
== Disease ==
[[http://www.uniprot.org/uniprot/BRD4_HUMAN 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.<ref>PMID:12543779</ref> <ref>PMID:11733348</ref>   
[[http://www.uniprot.org/uniprot/BRD4_HUMAN 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.<ref>PMID:12543779</ref> <ref>PMID:11733348</ref>   
 
== Function ==
==Function==
[[http://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).  
[[http://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Members of the bromodomain and extra terminal (BET) family of proteins are essential for the recognition of acetylated lysine (KAc) residues in histones and have emerged as promising drug targets in cancer, inflammation, and contraception research. In co-crystallization screening campaigns using the first bromodomain of BRD4 (BRD4-1) against kinase inhibitor libraries, we identified and characterized 14 kinase inhibitors (10 distinct chemical scaffolds) as ligands of the KAc binding site. Among these, the PLK1 inhibitor BI2536 and the JAK2 inhibitor TG101209 displayed strongest inhibitory potential against BRD4 (IC50 = 25 nM and 130 nM, respectively) and high selectivity for BET bromodomains. Comparative structural analysis revealed markedly different binding modes of kinase hinge-binding scaffolds in the KAc binding site, suggesting that BET proteins are potential off-targets of diverse kinase inhibitors. Combined, these findings provide a new structural framework for the rational design of next-generation BET-selective and dual-activity BET-kinase inhibitors.


==About this Structure==
Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4 (BRD4) Interacts with Diverse Kinase Inhibitors.,Ember SW, Zhu JY, Olesen SH, Martin MP, Becker A, Berndt N, Georg GI, Schonbrunn E ACS Chem Biol. 2014 Mar 13. PMID:24568369<ref>PMID:24568369</ref>
[[4o7b]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4O7B OCA].


==Reference==
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
<ref group="xtra">PMID:024568369</ref><references group="xtra"/><references/>
</div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Ember, S W.]]
[[Category: Ember, S W.]]
[[Category: Schonbrunn, E.]]
[[Category: Schonbrunn, E.]]

Revision as of 15:33, 18 May 2014

Crystal structure of the first bromodomain of human BRD4 in complex with SB-284847-BTCrystal structure of the first bromodomain of human BRD4 in complex with SB-284847-BT

Structural highlights

4o7b 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:,
Related:4o70, 4o71, 4o72, 4o73, 4o74, 4o75, 4o76, 4o77, 4o78, 4o7a, 4o7c, 4o7e, 4o7f
Gene:BRD4, HUNK1 (HUMAN)
Resources:FirstGlance, OCA, RCSB, PDBsum

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

Members of the bromodomain and extra terminal (BET) family of proteins are essential for the recognition of acetylated lysine (KAc) residues in histones and have emerged as promising drug targets in cancer, inflammation, and contraception research. In co-crystallization screening campaigns using the first bromodomain of BRD4 (BRD4-1) against kinase inhibitor libraries, we identified and characterized 14 kinase inhibitors (10 distinct chemical scaffolds) as ligands of the KAc binding site. Among these, the PLK1 inhibitor BI2536 and the JAK2 inhibitor TG101209 displayed strongest inhibitory potential against BRD4 (IC50 = 25 nM and 130 nM, respectively) and high selectivity for BET bromodomains. Comparative structural analysis revealed markedly different binding modes of kinase hinge-binding scaffolds in the KAc binding site, suggesting that BET proteins are potential off-targets of diverse kinase inhibitors. Combined, these findings provide a new structural framework for the rational design of next-generation BET-selective and dual-activity BET-kinase inhibitors.

Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4 (BRD4) Interacts with Diverse Kinase Inhibitors.,Ember SW, Zhu JY, Olesen SH, Martin MP, Becker A, Berndt N, Georg GI, Schonbrunn E ACS Chem Biol. 2014 Mar 13. PMID:24568369[3]

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

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ Ember SW, Zhu JY, Olesen SH, Martin MP, Becker A, Berndt N, Georg GI, Schonbrunn E. Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4 (BRD4) Interacts with Diverse Kinase Inhibitors. ACS Chem Biol. 2014 Mar 13. PMID:24568369 doi:http://dx.doi.org/10.1021/cb500072z

4o7b, resolution 1.50Å

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