6zb1: Difference between revisions

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<StructureSection load='6zb1' size='340' side='right'caption='[[6zb1]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
<StructureSection load='6zb1' size='340' side='right'caption='[[6zb1]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6zb1]] 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=6ZB1 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6ZB1 FirstGlance]. <br>
<table><tr><td colspan='2'>[[6zb1]] 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=6ZB1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZB1 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=QCZ:~{N}5-cyclopropyl-~{N}3-methyl-2-oxidanylidene-1-(phenylmethyl)pyridine-3,5-dicarboxamide'>QCZ</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]] 1.6&#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=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=QCZ:~{N}5-cyclopropyl-~{N}3-methyl-2-oxidanylidene-1-(phenylmethyl)pyridine-3,5-dicarboxamide'>QCZ</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6zb1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zb1 OCA], [http://pdbe.org/6zb1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6zb1 RCSB], [http://www.ebi.ac.uk/pdbsum/6zb1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6zb1 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=6zb1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zb1 OCA], [https://pdbe.org/6zb1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zb1 RCSB], [https://www.ebi.ac.uk/pdbsum/6zb1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zb1 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 ==
The profound efficacy, yet associated toxicity of pan-BET inhibitors is well documented. The possibility of an ameliorated safety profile driven by significantly selective (&gt;100 fold) inhibition of a sub-set of the 8 bromodomains is enticing, but challenging given the close homology. Herein, we describe the X-ray crystal structure-directed optimisation of a novel weak fragment ligand with a pan-second bromodomain (BD2) bias, to potent and highly BD2 selective inhibitors. A template hopping approach, enabled by our parallel research into an orthogonal template (15, GSK046) was the basis for the high selectivity observed. This culminated in two tool molecules 20 (GSK620) and 56 (GSK549) which showed an anti-inflammatory phenotype in human whole blood, confirming their cellular target engagement. Excellent broad selectivity, developability and in vivo oral pharmacokinetics characterize these tools, which we hope will be of broad utility to the field of epigenetics research.


The Optimisation of a Novel, Weak Bromo and Extra Terminal Domain (BET) Bromodomain Fragment Ligand to a Potent and Selective Second Bromodomain (BD2) Inhibitor.,Seal JT, Atkinson SJ, Aylott H, Bamborough P, Chung CW, Copley RCB, Gordon LJ, Grandi P, Gray JRJ, Harrison LA, Hayhow TG, Lindon M, Messenger C, Michon AM, Mitchell DJ, Preston A, Prinjha RK, Rioja I, Taylor S, Wall ID, Watson RJ, Woolven JM, Demont EH J Med Chem. 2020 Jul 23. doi: 10.1021/acs.jmedchem.0c00796. PMID:32702236<ref>PMID:32702236</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 6zb1" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Chung, C]]
[[Category: Chung C]]
[[Category: Antagonist]]
[[Category: Brd2]]
[[Category: Bromodomain]]
[[Category: Bromodomain containing protein 2]]
[[Category: Epigenetic reader]]
[[Category: Histone]]
[[Category: Inhibitor]]
[[Category: Transcription]]

Latest revision as of 10:40, 1 May 2024

C-TERMINAL BROMODOMAIN OF HUMAN BRD2 WITH GSK620C-TERMINAL BROMODOMAIN OF HUMAN BRD2 WITH GSK620

Structural highlights

6zb1 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 1.6Å
Ligands:,
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]

See Also

References

  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

6zb1, resolution 1.60Å

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OCA
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