View source for 5f62


==Crystal structure of the first bromodomain of human BRD4 in complex with MA4-022-2==
<StructureSection load='5f62' size='340' side='right'caption='[[5f62]], [[Resolution|resolution]] 1.35&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5f62]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5F62 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5F62 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.35&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5W1:~{N}-[2-CHLORANYL-5-[[2-[[3-FLUORANYL-4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO]-5-METHYL-PYRIMIDIN-4-YL]AMINO]PHENYL]-2-METHYL-PROPANE-2-SULFONAMIDE'>5W1</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5f62 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5f62 OCA], [https://pdbe.org/5f62 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5f62 RCSB], [https://www.ebi.ac.uk/pdbsum/5f62 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5f62 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://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 ==
[https://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 ==
Synergistic action of kinase and BET bromodomain inhibitors in cell killing has been reported for a variety of cancers. Using the chemical scaffold of the JAK2 inhibitor TG101348 we developed and characterized single agents which potently and simultaneously inhibit BRD4 and a specific set of oncogenic tyrosine kinases including JAK2, FLT3, RET, and ROS1. Lead compounds showed on-target inhibition in several blood cancer cell lines and were highly efficacious at inhibiting the growth of hematopoietic progenitor cells from myeloproliferative neoplasm (MPN) patients. Screening across 931 cancer cell lines revealed differential growth inhibitory potential with highest activity against bone and blood cancers, and greatly enhanced activity over the single BET inhibitor JQ1. Gene-drug sensitivity analyses and drug combination studies indicate synergism of BRD4 and kinase inhibition as a plausible reason for the superior potency in cell killing. Combined, our findings indicate promising potential of these agents as novel chemical probes and cancer therapeutics.

Potent dual BET bromodomain-kinase inhibitors as value added multi-targeted chemical probes and cancer therapeutics.,Ember SW, Lambert QT, Berndt N, Gunawan S, Ayaz M, Tauro M, Zhu JY, Cranfill PJ, Greninger P, Lynch CC, Benes CH, Lawrence HR, Reuther GW, Lawrence NJ, Schonbrunn E Mol Cancer Ther. 2017 Mar 23. pii: molcanther.0568.2016. doi:, 10.1158/1535-7163.MCT-16-0568-T. PMID:28336808<ref>PMID:28336808</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5f62" style="background-color:#fffaf0;"></div>

==See Also==
*[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Ember SW]]
[[Category: Schonbrunn E]]
[[Category: Zhu J-Y]]