6k05: Difference between revisions

Latest revision as of 10:23, 22 November 2023

Crystal structure of BRD2(BD1)with ligand BY27 bound

Structural highlights

6k05 is a 3 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 1.935Å
Ligands:	CQF, MES
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.^[1]

Publication Abstract from PubMed

Recently, selective inhibition of BET BD2 is emerging as a promising strategy for drug discovery. Despite significant progress in this area, systematic studies of selective BET BD2 inhibitors are still few. In this study, we report the discovery of a potent and selective BET BD2 inhibitor BY27 (47). Our high resolution co-crystal structures of 47/BRD2 BD1 and BD2 showed that the triazole group of 47, water molecules, H433 and N429 in BRD2 BD2 established a water-bridged H-bonding network, which is responsible for the observed selectivities. DNA microarray analysis of HepG2 cells treated with 47 or OTX015 demonstrated the transcriptome impact differences between a BET BD2 selective inhibitor and a pan BET inhibitor. In a MV4-11 mouse xenograft model, 47 caused 67% of tumor growth inhibition and was less toxic than a pan BET inhibitor 1â¯at high doses. We conclude that the improved safety profile of selective BET BD2 inhibitors warrant future studies in BET associated diseases.

Discovery, structural insight, and bioactivities of BY27 as a selective inhibitor of the second bromodomains of BET proteins.,Chen D, Lu T, Yan Z, Lu W, Zhou F, Lyu X, Xu B, Jiang H, Chen K, Luo C, Zhao Y Eur J Med Chem. 2019 Nov 15;182:111633. doi: 10.1016/j.ejmech.2019.111633. Epub , 2019 Aug 21. PMID:31461688^[2]

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

References

↑ LeRoy G, Rickards B, Flint SJ. The double bromodomain proteins Brd2 and Brd3 couple histone acetylation to transcription. Mol Cell. 2008 Apr 11;30(1):51-60. doi: 10.1016/j.molcel.2008.01.018. PMID:18406326 doi:10.1016/j.molcel.2008.01.018
↑ Chen D, Lu T, Yan Z, Lu W, Zhou F, Lyu X, Xu B, Jiang H, Chen K, Luo C, Zhao Y. Discovery, structural insight, and bioactivities of BY27 as a selective inhibitor of the second bromodomains of BET proteins. Eur J Med Chem. 2019 Nov 15;182:111633. PMID:31461688 doi:10.1016/j.ejmech.2019.111633

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OCA

[1] LeRoy G, Rickards B, Flint SJ. The double bromodomain proteins Brd2 and Brd3 couple histone acetylation to transcription. Mol Cell. 2008 Apr 11;30(1):51-60. doi: 10.1016/j.molcel.2008.01.018. PMID:18406326 doi:10.1016/j.molcel.2008.01.018

[2] Chen D, Lu T, Yan Z, Lu W, Zhou F, Lyu X, Xu B, Jiang H, Chen K, Luo C, Zhao Y. Discovery, structural insight, and bioactivities of BY27 as a selective inhibitor of the second bromodomains of BET proteins. Eur J Med Chem. 2019 Nov 15;182:111633. PMID:31461688 doi:10.1016/j.ejmech.2019.111633

[1]

[2]

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6k05 is ON HOLD
+==Crystal structure of BRD2(BD1)with ligand BY27 bound==
+<StructureSection load='6k05' size='340' side='right'caption='[[6k05]], [[Resolution|resolution]] 1.94&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6k05]] is a 3 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=6K05 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6K05 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]] 1.935&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CQF:(6~{R})-~{N}-(4-chlorophenyl)-1-methyl-8-(1-methylpyrazol-4-yl)-5,6-dihydro-4~{H}-[1,2,4]triazolo[4,3-a][1]benzazepin-6-amine'>CQF</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</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=6k05 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6k05 OCA], [https://pdbe.org/6k05 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6k05 RCSB], [https://www.ebi.ac.uk/pdbsum/6k05 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6k05 ProSAT]</span></td></tr>
+</table>
+== Function ==
+[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 ==
+Recently, selective inhibition of BET BD2 is emerging as a promising strategy for drug discovery. Despite significant progress in this area, systematic studies of selective BET BD2 inhibitors are still few. In this study, we report the discovery of a potent and selective BET BD2 inhibitor BY27 (47). Our high resolution co-crystal structures of 47/BRD2 BD1 and BD2 showed that the triazole group of 47, water molecules, H433 and N429 in BRD2 BD2 established a water-bridged H-bonding network, which is responsible for the observed selectivities. DNA microarray analysis of HepG2 cells treated with 47 or OTX015 demonstrated the transcriptome impact differences between a BET BD2 selective inhibitor and a pan BET inhibitor. In a MV4-11 mouse xenograft model, 47 caused 67% of tumor growth inhibition and was less toxic than a pan BET inhibitor 1â¯at high doses. We conclude that the improved safety profile of selective BET BD2 inhibitors warrant future studies in BET associated diseases.
-Authors: Lu, T., Lu, W., Chen, D., Zhao, Y., Luo, C.
+Discovery, structural insight, and bioactivities of BY27 as a selective inhibitor of the second bromodomains of BET proteins.,Chen D, Lu T, Yan Z, Lu W, Zhou F, Lyu X, Xu B, Jiang H, Chen K, Luo C, Zhao Y Eur J Med Chem. 2019 Nov 15;182:111633. doi: 10.1016/j.ejmech.2019.111633. Epub , 2019 Aug 21. PMID:31461688<ref>PMID:31461688</ref>
-Description: Crystal structure of BRD2(BD1)with ligand BY27 bound
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Chen, D]]
+<div class="pdbe-citations 6k05" style="background-color:#fffaf0;"></div>
-[[Category: Lu, W]]
-[[Category: Luo, C]]
+==See Also==
-[[Category: Lu, T]]
+*[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]]
-[[Category: Zhao, Y]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Chen D]]
+[[Category: Lu T]]
+[[Category: Lu W]]
+[[Category: Luo C]]
+[[Category: Zhao Y]]

6k05: Difference between revisions

Latest revision as of 10:23, 22 November 2023

Crystal structure of BRD2(BD1)with ligand BY27 bound

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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