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6czv

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==BRD4(BD1) complexed with 2759==
==BRD4(BD1) complexed with 2759==
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<StructureSection load='6czv' size='340' side='right' caption='[[6czv]], [[Resolution|resolution]] 1.88&Aring;' scene=''>
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<StructureSection load='6czv' size='340' side='right'caption='[[6czv]], [[Resolution|resolution]] 1.88&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6czv]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CZV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CZV FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6czv]] 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=6CZV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6CZV FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FOY:1-benzyl-5-(3,5-dimethyl-1,2-oxazol-4-yl)pyridin-2(1H)-one'>FOY</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.88&#8491;</td></tr>
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<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=6czv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6czv OCA], [http://pdbe.org/6czv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6czv RCSB], [http://www.ebi.ac.uk/pdbsum/6czv PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6czv ProSAT]</span></td></tr>
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<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=FOY:1-benzyl-5-(3,5-dimethyl-1,2-oxazol-4-yl)pyridin-2(1H)-one'>FOY</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6czv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6czv OCA], [https://pdbe.org/6czv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6czv RCSB], [https://www.ebi.ac.uk/pdbsum/6czv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6czv ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
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[[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>
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[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 ==
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[[http://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).
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[https://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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BET proteins are key epigenetic regulators that regulate transcription through binding to acetylated lysine (AcLys) residues of histones and transcription factors through bromodomains (BDs). The disruption of this interaction with small molecule bromodomain inhibitors is a promising approach to treat various diseases including cancer, autoimmune and cardiovascular diseases. Covalent inhibitors can potentially offer a more durable target inhibition leading to improved in vivo pharmacology. Here we describe the design of covalent inhibitors of BRD4(BD1) that target a methionine in the binding pocket by attaching an epoxide warhead to a suitably oriented noncovalent inhibitor. Using thermal denaturation, MALDI-TOF mass spectrometry, and an X-ray crystal structure, we demonstrate that these inhibitors selectively form a covalent bond with Met149 in BRD4(BD1) but not other bromodomains and provide durable transcriptional and antiproliferative activity in cell based assays. Covalent targeting of methionine offers a novel approach to drug discovery for BET proteins and other targets.
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Design and Characterization of Novel Covalent Bromodomain and Extra-Terminal Domain (BET) Inhibitors Targeting a Methionine.,Kharenko OA, Patel RG, Brown SD, Calosing C, White A, Lakshminarasimhan D, Suto RK, Duffy BC, Kitchen DB, McLure KG, Hansen HC, van der Horst EH, Young PR J Med Chem. 2018 Sep 13. doi: 10.1021/acs.jmedchem.8b00666. PMID:30165024<ref>PMID:30165024</ref>
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==See Also==
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*[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]]
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 6czv" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Lakshminarasimhan, D]]
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[[Category: Homo sapiens]]
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[[Category: Suto, R K]]
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[[Category: Large Structures]]
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[[Category: White, A]]
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[[Category: Lakshminarasimhan D]]
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[[Category: Bromodomain]]
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[[Category: Suto RK]]
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[[Category: Transcription-inhibitor complex]]
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[[Category: White A]]

Current revision

BRD4(BD1) complexed with 2759

PDB ID 6czv

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