7c6p: Difference between revisions
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==Bromodomain-containing 4 BD2 in complex with 3',4',7,8- Tetrahydroxyflavonoid== | ==Bromodomain-containing 4 BD2 in complex with 3',4',7,8- Tetrahydroxyflavonoid== | ||
<StructureSection load='7c6p' size='340' side='right'caption='[[7c6p]]' scene=''> | <StructureSection load='7c6p' size='340' side='right'caption='[[7c6p]], [[Resolution|resolution]] 1.73Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7C6P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7C6P FirstGlance]. <br> | <table><tr><td colspan='2'>[[7c6p]] 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=7C6P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7C6P FirstGlance]. <br> | ||
</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=7c6p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7c6p OCA], [https://pdbe.org/7c6p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7c6p RCSB], [https://www.ebi.ac.uk/pdbsum/7c6p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7c6p ProSAT]</span></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]] 1.73Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SQH:2-[3,4-bis(oxidanyl)phenyl]-7,8-bis(oxidanyl)chromen-4-one'>SQH</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=7c6p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7c6p OCA], [https://pdbe.org/7c6p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7c6p RCSB], [https://www.ebi.ac.uk/pdbsum/7c6p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7c6p ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== 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 == | |||
[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 == | |||
Bromodomain-containing protein 4 (BRD4) binds acetylated lysine residues on the N-terminal tails of histones through two bromodomains (BD1 and BD2) to regulate gene transcription. Inhibiting one or both of bromodomains resulted in different phenotypes, suggesting BD1 and BD2 may have different functions. Here we report the characterisation of a natural product 3',4',7,8-tetrahydroxyflavone as a novel and potent selective BRD4 inhibitor. The compound is 100-fold more selective for BRD4-BD2 (IC50 = 204 nM) than BRD4-BD1 (IC50=17.9 microM). Co-crystal structures show 3',4',7,8-tetrahydroxyflavone binds to the acetylated lysine binding pocket of BRD4-BD1 or BRD4-BD2, but establishes more interactions with BRD4-BD2 than BRD4-BD1. Our data suggest 3',4',7,8-tetrahydroxyflavone as a potent selective inhibitor of BRD4-BD2 with a novel chemical scaffold. Given its distinct chemical structure from current BRD4 inhibitors, this compound may open the door for a novel class of anti-BRD4 inhibitors by serving as a lead compound. | |||
Discovery of the natural product 3',4',7,8-tetrahydroxyflavone as a novel and potent selective BRD4 bromodomain 2 inhibitor.,Li J, Zou W, Yu K, Liu B, Liang W, Wang L, Lu Y, Jiang Z, Wang A, Zhu J J Enzyme Inhib Med Chem. 2021 Dec;36(1):903-913. doi:, 10.1080/14756366.2021.1906663. PMID:33820450<ref>PMID:33820450</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7c6p" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Li J]] | [[Category: Li J]] | ||
Latest revision as of 18:57, 29 November 2023
Bromodomain-containing 4 BD2 in complex with 3',4',7,8- TetrahydroxyflavonoidBromodomain-containing 4 BD2 in complex with 3',4',7,8- Tetrahydroxyflavonoid
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 PubMedBromodomain-containing protein 4 (BRD4) binds acetylated lysine residues on the N-terminal tails of histones through two bromodomains (BD1 and BD2) to regulate gene transcription. Inhibiting one or both of bromodomains resulted in different phenotypes, suggesting BD1 and BD2 may have different functions. Here we report the characterisation of a natural product 3',4',7,8-tetrahydroxyflavone as a novel and potent selective BRD4 inhibitor. The compound is 100-fold more selective for BRD4-BD2 (IC50 = 204 nM) than BRD4-BD1 (IC50=17.9 microM). Co-crystal structures show 3',4',7,8-tetrahydroxyflavone binds to the acetylated lysine binding pocket of BRD4-BD1 or BRD4-BD2, but establishes more interactions with BRD4-BD2 than BRD4-BD1. Our data suggest 3',4',7,8-tetrahydroxyflavone as a potent selective inhibitor of BRD4-BD2 with a novel chemical scaffold. Given its distinct chemical structure from current BRD4 inhibitors, this compound may open the door for a novel class of anti-BRD4 inhibitors by serving as a lead compound. Discovery of the natural product 3',4',7,8-tetrahydroxyflavone as a novel and potent selective BRD4 bromodomain 2 inhibitor.,Li J, Zou W, Yu K, Liu B, Liang W, Wang L, Lu Y, Jiang Z, Wang A, Zhu J J Enzyme Inhib Med Chem. 2021 Dec;36(1):903-913. doi:, 10.1080/14756366.2021.1906663. PMID:33820450[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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