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==Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor PFi-1==
==Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor PFi-1==
<StructureSection load='4e96' size='340' side='right' caption='[[4e96]], [[Resolution|resolution]] 1.92&Aring;' scene=''>
<StructureSection load='4e96' size='340' side='right'caption='[[4e96]], [[Resolution|resolution]] 1.92&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4e96]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4E96 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4E96 FirstGlance]. <br>
<table><tr><td colspan='2'>[[4e96]] 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=4E96 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4E96 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0NS:2-METHOXY-N-(3-METHYL-2-OXO-1,2,3,4-TETRAHYDROQUINAZOLIN-6-YL)BENZENESULFONAMIDE'>0NS</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.92&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2oss|2oss]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0NS:2-METHOXY-N-(3-METHYL-2-OXO-1,2,3,4-TETRAHYDROQUINAZOLIN-6-YL)BENZENESULFONAMIDE'>0NS</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
<tr id='gene'><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 Homo sapiens])</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=4e96 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e96 OCA], [https://pdbe.org/4e96 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4e96 RCSB], [https://www.ebi.ac.uk/pdbsum/4e96 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4e96 ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4e96 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e96 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4e96 RCSB], [http://www.ebi.ac.uk/pdbsum/4e96 PDBsum]</span></td></tr>
</table>
</table>
== Disease ==
== 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>
[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 ==
[[http://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).  
[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 ==
The posttranslational modification of chromatin through acetylation at selected histone lysine residues is governed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). The significance of this subset of the epigenetic code is interrogated and interpreted by an acetyllysine-specific protein-protein interaction with bromodomain reader modules. Selective inhibition of the bromo and extra C-terminal domain (BET) family of bromodomains with a small molecule is feasible, and this may represent an opportunity for disease intervention through the recently disclosed antiproliferative and anti-inflammatory properties of such inhibitors. Herein, we describe the discovery and structure-activity relationship (SAR) of a novel, small-molecule chemical probe for BET family inhibition that was identified through the application of structure-based fragment assessment and optimization techniques. This has yielded a potent, selective compound with cell-based activity (PFI-1) that may further add to the understanding of BET family function within the bromodomains.
 
Identification of a Chemical Probe for Bromo and Extra C-Terminal Bromodomain Inhibition through Optimization of a Fragment-Derived Hit.,Fish PV, Filippakopoulos P, Bish G, Brennan PE, Bunnage ME, Cook AS, Federov O, Gerstenberger BS, Jones H, Knapp S, Marsden B, Nocka K, Owen DR, Philpott M, Picaud S, Primiano MJ, Ralph MJ, Sciammetta N, Trzupek JD J Med Chem. 2012 Nov 8. PMID:23095041<ref>PMID:23095041</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>


==See Also==
==See Also==
*[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]]
*[[Multiple sclerosis|Multiple sclerosis]]
*[[Multiple sclerosis|Multiple sclerosis]]
== References ==
== References ==
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</StructureSection>
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Arrowsmith, C H]]
[[Category: Large Structures]]
[[Category: Bunnage, M]]
[[Category: Arrowsmith CH]]
[[Category: Cook, A]]
[[Category: Bunnage M]]
[[Category: Delft, F von]]
[[Category: Cook A]]
[[Category: Edwards, A M]]
[[Category: Edwards AM]]
[[Category: Fedorov, O]]
[[Category: Fedorov O]]
[[Category: Felletar, I]]
[[Category: Felletar I]]
[[Category: Filippakopoulos, P]]
[[Category: Filippakopoulos P]]
[[Category: Fish, P]]
[[Category: Fish P]]
[[Category: Knapp, S]]
[[Category: Knapp S]]
[[Category: Owen, D]]
[[Category: Owen D]]
[[Category: Picaud, S]]
[[Category: Picaud S]]
[[Category: Structural genomic]]
[[Category: Weigelt J]]
[[Category: Weigelt, J]]
[[Category: Von Delft F]]
[[Category: Betsoff1]]
[[Category: Bromodomain]]
[[Category: Cap]]
[[Category: Cell cycle]]
[[Category: Hunk1]]
[[Category: Jq1]]
[[Category: Mcap]]
[[Category: Mitotic chromosome associated protein]]
[[Category: Protein binding-inhibitor complex]]
[[Category: Sgc]]

Latest revision as of 17:55, 14 March 2024

Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor PFi-1Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor PFi-1

Structural highlights

4e96 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.92Å
Ligands:, , ,
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.[1] [2]

Function

BRD4_HUMAN Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).

See Also

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

4e96, resolution 1.92Å

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