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==Crystal Structure of the first bromodomain of human BRD4 in complex with a 3,5-dimethylisoxazol ligand== | ==Crystal Structure of the first bromodomain of human BRD4 in complex with a 3,5-dimethylisoxazol ligand== | ||
<StructureSection load='4j0r' size='340' side='right' caption='[[4j0r]], [[Resolution|resolution]] 1.72Å' scene=''> | <StructureSection load='4j0r' size='340' side='right'caption='[[4j0r]], [[Resolution|resolution]] 1.72Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4j0r]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[4j0r]] 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=4J0R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4J0R FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1H2:3-(3,5-DIMETHYL-1,2-OXAZOL-4-YL)-5-[(R)-HYDROXY(PHENYL)METHYL]PHENOL'>1H2</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.72Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1H2:3-(3,5-DIMETHYL-1,2-OXAZOL-4-YL)-5-[(R)-HYDROXY(PHENYL)METHYL]PHENOL'>1H2</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</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=4j0r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4j0r OCA], [https://pdbe.org/4j0r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4j0r RCSB], [https://www.ebi.ac.uk/pdbsum/4j0r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4j0r ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Disease == | == 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 == | == 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;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 24: | Line 23: | ||
==See Also== | ==See Also== | ||
*[[Bromodomain-containing protein|Bromodomain-containing protein]] | *[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Arrowsmith CH]] | ||
[[Category: | [[Category: Bountra C]] | ||
[[Category: | [[Category: Conway SJ]] | ||
[[Category: Edwards | [[Category: Edwards A]] | ||
[[Category: Felletar | [[Category: Felletar I]] | ||
[[Category: Filippakopoulos | [[Category: Filippakopoulos P]] | ||
[[Category: Hewings | [[Category: Hewings DS]] | ||
[[Category: Knapp | [[Category: Knapp S]] | ||
[[Category: Picaud | [[Category: Picaud S]] | ||
[[Category: Qi | [[Category: Qi J]] | ||
[[Category: | [[Category: Von Delft F]] | ||
Latest revision as of 18:34, 20 September 2023
Crystal Structure of the first bromodomain of human BRD4 in complex with a 3,5-dimethylisoxazol ligandCrystal Structure of the first bromodomain of human BRD4 in complex with a 3,5-dimethylisoxazol ligand
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 PubMedThe bromodomain protein module, which binds to acetylated lysine, is emerging as an important epigenetic therapeutic target. We report the structure-guided optimization of 3,5-dimethylisoxazole derivatives to develop potent inhibitors of the BET (bromodomain and extra terminal domain) bromodomain family with good ligand efficiency. X-ray crystal structures of the most potent compounds reveal key interactions required for high affinity at BRD4(1). Cellular studies demonstrate that the phenol and acetate derivatives of the lead compounds showed strong antiproliferative effects on MV4;11 acute myeloid leukemia cells, as shown for other BET bromodomain inhibitors and genetic BRD4 knockdown, whereas the reported compounds showed no general cytotoxicity in other cancer cell lines tested. Optimization of 3,5-dimethylisoxazole derivatives as potent bromodomain ligands.,Hewings DS, Fedorov O, Filippakopoulos P, Martin S, Picaud S, Tumber A, Wells C, Olcina MM, Freeman K, Gill A, Ritchie AJ, Sheppard DW, Russell AJ, Hammond EM, Knapp S, Brennan PE, Conway SJ J Med Chem. 2013 Apr 25;56(8):3217-27. doi: 10.1021/jm301588r. Epub 2013 Apr 5. PMID:23517011[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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