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6mh1

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CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH HU-10, A 1,4,5-Trisubstituted Imidazole Analogue

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Retrieved from "http://52.214.119.220/wiki/index.php/6mh1"

Categories: Homo sapiens | Large Structures | Schonbrunn E | Zhu J-Y

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 <StructureSection load='6mh1' size='340' side='right'caption='[[6mh1]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6mh1]] is a 2 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=6MH1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MH1 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6mh1]] is a 2 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=6MH1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6MH1 FirstGlance]. <br>
-</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=JQP:N-(3,5-dimethylphenyl)-4-[4-(4-fluorophenyl)-1-(piperidin-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine'>JQP</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">BRD4, HUNK1 ([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=JQP:N-(3,5-dimethylphenyl)-4-[4-(4-fluorophenyl)-1-(piperidin-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine'>JQP</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=6mh1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mh1 OCA], [http://pdbe.org/6mh1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6mh1 RCSB], [http://www.ebi.ac.uk/pdbsum/6mh1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6mh1 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=6mh1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mh1 OCA], [https://pdbe.org/6mh1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6mh1 RCSB], [https://www.ebi.ac.uk/pdbsum/6mh1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6mh1 ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[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>
+[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 ==
-[[http://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).
+[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 ==
-As regulators of transcription, epigenetic proteins that interpret post-translational modifications to N-terminal histone tails are essential for maintaining cellular homeostasis. When dysregulated, "reader" proteins become drivers of disease. In the case of bromodomains, which recognize N-epsilon-acetylated lysine, selective inhibition of individual bromodomain-and-extra-terminal (BET)-family bromodomains has proven challenging. We describe the &gt;55-fold N-terminal-BET bromodomain selectivity of 1,4,5-trisubstituted-imidazole dual kinase-bromodomain inhibitors. Selectivity for the BRD4 N-terminal bromodomain (BRD4(1)) over its second bromodomain (BRD4(2)) arises from the displacement of ordered waters and the conformational flexibility of lysine-141 in BRD4(1). Cellular efficacy was demonstrated via reduction of c-Myc expression, inhibition of NF-kappaB signaling, and suppression of IL-8 production through potential synergistic inhibition of BRD4(1) and p38alpha. These dual inhibitors provide a new scaffold for domain-selective inhibition of BRD4, the aberrant function of which plays a key role in cancer and inflammatory signaling.
-Molecular Basis for the N-Terminal Bromodomain-and-Extra-Terminal-Family Selectivity of a Dual Kinase-Bromodomain Inhibitor.,Divakaran A, Talluri SK, Ayoub AM, Mishra NK, Cui H, Widen JC, Berndt N, Zhu JY, Carlson AS, Topczewski JJ, Schonbrunn EK, Harki DA, Pomerantz WCK J Med Chem. 2018 Oct 25;61(20):9316-9334. doi: 10.1021/acs.jmedchem.8b01248. Epub, 2018 Oct 16. PMID:30253095<ref>PMID:30253095</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 6mh1" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Schonbrunn, E]]
+[[Category: Schonbrunn E]]
-[[Category: Zhu, J Y]]
+[[Category: Zhu J-Y]]
-[[Category: Cap]]
-[[Category: Hunk1]]
-[[Category: Inflammation]]
-[[Category: Inhibitor]]
-[[Category: Map-kinase inhibition]]
-[[Category: Mcap]]
-[[Category: Protein binding-inhibitor complex]]
-[[Category: Transcription-inhibitor complex]]
-[[Category: Transcription-transcription inhibitor complex]]

6mh1

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CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH HU-10, A 1,4,5-Trisubstituted Imidazole Analogue

Structural highlights

Disease

Function

See Also

References

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