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==X-ray crystal structure of 1,2,3-triazolobenzodiazepine in complex with BRD2(D2)==
==X-ray crystal structure of 1,2,3-triazolobenzodiazepine in complex with BRD2(D2)==
<StructureSection load='5u6v' size='340' side='right' caption='[[5u6v]], [[Resolution|resolution]] 1.77&Aring;' scene=''>
<StructureSection load='5u6v' size='340' side='right'caption='[[5u6v]], [[Resolution|resolution]] 1.77&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[5u6v]] 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=5U6V OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5U6V FirstGlance]. <br>
<table><tr><td colspan='2'>[[5u6v]] 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=5U6V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5U6V FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7WY:5-[7-(4-chlorophenyl)-1-methyl-6,7-dihydro-5H-[1,2,3]triazolo[1,5-d][1,4]benzodiazepin-9-yl]pyridin-2-amine'>7WY</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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]] 1.775&#8491;</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BRD2, KIAA9001, RING3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7WY:5-[7-(4-chlorophenyl)-1-methyl-6,7-dihydro-5H-[1,2,3]triazolo[1,5-d][1,4]benzodiazepin-9-yl]pyridin-2-amine'>7WY</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5u6v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5u6v OCA], [http://pdbe.org/5u6v PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5u6v RCSB], [http://www.ebi.ac.uk/pdbsum/5u6v PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5u6v ProSAT]</span></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=5u6v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5u6v OCA], [https://pdbe.org/5u6v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5u6v RCSB], [https://www.ebi.ac.uk/pdbsum/5u6v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5u6v ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/BRD2_HUMAN BRD2_HUMAN]] May play a role in spermatogenesis or folliculogenesis (By similarity). Binds hyperacetylated chromatin and plays a role in the regulation of transcription, probably by chromatin remodeling. Regulates transcription of the CCND1 gene. Plays a role in nucleosome assembly.<ref>PMID:18406326</ref>
[https://www.uniprot.org/uniprot/BRD2_HUMAN BRD2_HUMAN] May play a role in spermatogenesis or folliculogenesis (By similarity). Binds hyperacetylated chromatin and plays a role in the regulation of transcription, probably by chromatin remodeling. Regulates transcription of the CCND1 gene. Plays a role in nucleosome assembly.<ref>PMID:18406326</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
A number of diazepines are known to inhibit bromo- and extra-terminal domain (BET) proteins. Their BET inhibitory activity derives from the fusion of an acetyl-lysine mimetic heterocycle onto the diazepine framework. Herein we describe a straightforward, modular synthesis of novel 1,2,3-triazolobenzodiazepines and show that the 1,2,3-triazole acts as an effective acetyl-lysine mimetic heterocycle. Structure-based optimization of this series of compounds led to the development of potent BET bromodomain inhibitors with excellent activity against leukemic cells, concomitant with a reduction in c-MYC expression. These novel benzodiazepines therefore represent a promising class of therapeutic BET inhibitors.


Design, Synthesis, and Biological Activity of 1,2,3-Triazolobenzodiazepine BET Bromodomain Inhibitors.,Sharp PP, Garnier JM, Hatfaludi T, Xu Z, Segal D, Jarman KE, Jousset H, Garnham A, Feutrill JT, Cuzzupe A, Hall P, Taylor S, Walkley CR, Tyler D, Dawson MA, Czabotar P, Wilks AF, Glaser S, Huang DCS, Burns CJ ACS Med Chem Lett. 2017 Nov 14;8(12):1298-1303. doi:, 10.1021/acsmedchemlett.7b00389. eCollection 2017 Dec 14. PMID:29259751<ref>PMID:29259751</ref>
==See Also==
 
*[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]]
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5u6v" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Burns, C J]]
[[Category: Large Structures]]
[[Category: Czabotar, P E]]
[[Category: Burns CJ]]
[[Category: Garnier, J M]]
[[Category: Czabotar PE]]
[[Category: Hatfaludi, T]]
[[Category: Garnier J-M]]
[[Category: Sharp, P P]]
[[Category: Hatfaludi T]]
[[Category: Benzodiazepine]]
[[Category: Sharp PP]]
[[Category: Bromodomain]]
[[Category: Epigenetic]]
[[Category: Transcription-transcription inhibitor complex]]

Latest revision as of 14:25, 6 March 2024

X-ray crystal structure of 1,2,3-triazolobenzodiazepine in complex with BRD2(D2)

5u6v, resolution 1.77Å

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