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| | <StructureSection load='5ti5' size='340' side='right'caption='[[5ti5]], [[Resolution|resolution]] 1.83Å' scene=''> | | <StructureSection load='5ti5' size='340' side='right'caption='[[5ti5]], [[Resolution|resolution]] 1.83Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5ti5]] 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=5TI5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TI5 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5ti5]] 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=5TI5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TI5 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7CN:3-bromo-N-[3-(2-oxo-2,3-dihydro-1H-pyrrol-1-yl)phenyl]benzene-1-sulfonamide'>7CN</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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]] 1.83Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5ti2|5ti2]], [[5ti3|5ti3]], [[5ti4|5ti4]], [[5ti6|5ti6]], [[5ti7|5ti7]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7CN:3-bromo-N-[3-(2-oxo-2,3-dihydro-1H-pyrrol-1-yl)phenyl]benzene-1-sulfonamide'>7CN</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5ti5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ti5 OCA], [https://pdbe.org/5ti5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ti5 RCSB], [https://www.ebi.ac.uk/pdbsum/5ti5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ti5 ProSAT]</span></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=5ti5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ti5 OCA], [http://pdbe.org/5ti5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ti5 RCSB], [http://www.ebi.ac.uk/pdbsum/5ti5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ti5 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == 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 == | | == 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 ==
| + | |
| - | Computational screening is a method to prioritize small-molecule compounds based on the structural and biochemical attributes built from ligand and target information. Previously, we have developed a scalable virtual screening workflow to identify novel multitarget kinase/bromodomain inhibitors. In the current study, we identified several novel N-[3-(2-oxo-pyrrolidinyl)phenyl]-benzenesulfonamide derivatives that scored highly in our ensemble docking protocol. We quantified the binding affinity of these compounds for BRD4(BD1) biochemically and generated cocrystal structures, which were deposited in the Protein Data Bank. As the docking poses obtained in the virtual screening pipeline did not align with the experimental cocrystal structures, we evaluated the predictions of their precise binding modes by performing molecular dynamics (MD) simulations. The MD simulations closely reproduced the experimentally observed protein-ligand cocrystal binding conformations and interactions for all compounds. These results suggest a computational workflow to generate experimental-quality protein-ligand binding models, overcoming limitations of docking results due to receptor flexibility and incomplete sampling, as a useful starting point for the structure-based lead optimization of novel BRD4(BD1) inhibitors.
| + | |
| - | | + | |
| - | Identification of a Novel Class of BRD4 Inhibitors by Computational Screening and Binding Simulations.,Allen BK, Mehta S, Ember SWJ, Zhu JY, Schonbrunn E, Ayad NG, Schurer SC ACS Omega. 2017 Aug 31;2(8):4760-4771. doi: 10.1021/acsomega.7b00553. Epub 2017, Aug 21. PMID:28884163<ref>PMID:28884163</ref>
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| - | | + | |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| - | </div>
| + | |
| - | <div class="pdbe-citations 5ti5" style="background-color:#fffaf0;"></div>
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| | | | |
| | ==See Also== | | ==See Also== |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Ember, S W.J]] | + | [[Category: Ember SWJ]] |
| - | [[Category: Schonbrunn, E]] | + | [[Category: Schonbrunn E]] |
| - | [[Category: Zhu, J Y]] | + | [[Category: Zhu J-Y]] |
| - | [[Category: Bromodomain]]
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| - | [[Category: Cap]]
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| - | [[Category: Cell cycle]]
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| - | [[Category: Hunk1]]
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| - | [[Category: Inhibitor]]
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| - | [[Category: Mcap]]
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| - | [[Category: Mitotic chromosome associated protein]]
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| - | [[Category: Protein binding-inhibitor complex]]
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| - | [[Category: Transcription-inhibitor complex]]
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