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| | ==CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH INHIBITOR 8841871== | | ==CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH INHIBITOR 8841871== |
| - | <StructureSection load='5ti4' size='340' side='right' caption='[[5ti4]], [[Resolution|resolution]] 1.62Å' scene=''> | + | <StructureSection load='5ti4' size='340' side='right'caption='[[5ti4]], [[Resolution|resolution]] 1.62Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5ti4]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TI4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TI4 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5ti4]] 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=5TI4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TI4 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7CM:3-chloro-4-fluoro-N-[3-(2-oxopyrrolidin-1-yl)phenyl]benzene-1-sulfonamide'>7CM</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]] 1.62Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5ti2|5ti2]], [[5ti3|5ti3]], [[5ti5|5ti5]], [[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=7CM:3-chloro-4-fluoro-N-[3-(2-oxopyrrolidin-1-yl)phenyl]benzene-1-sulfonamide'>7CM</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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=5ti4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ti4 OCA], [http://pdbe.org/5ti4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ti4 RCSB], [http://www.ebi.ac.uk/pdbsum/5ti4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ti4 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=5ti4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ti4 OCA], [https://pdbe.org/5ti4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ti4 RCSB], [https://www.ebi.ac.uk/pdbsum/5ti4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ti4 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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5ti4" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5ti4" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Ember, S W.J]] | + | [[Category: Homo sapiens]] |
| - | [[Category: SCHONBRUNN, E]] | + | [[Category: Large Structures]] |
| - | [[Category: Zhu, J Y]] | + | [[Category: Ember SWJ]] |
| - | [[Category: Bromodomain]] | + | [[Category: SCHONBRUNN E]] |
| - | [[Category: Cap]] | + | [[Category: Zhu J-Y]] |
| - | [[Category: Cell cycle]]
| + | |
| - | [[Category: Hunk1]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Mcap]]
| + | |
| - | [[Category: Mitotic chromosome associated protein]]
| + | |
| - | [[Category: Protein binding-inhibitor complex]]
| + | |
| - | [[Category: Transcription-inhibitor complex]]
| + | |
| Structural highlights
Disease
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.[1] [2]
Function
BRD4_HUMAN Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).
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[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ French CA, Miyoshi I, Kubonishi I, Grier HE, Perez-Atayde AR, Fletcher JA. BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma. Cancer Res. 2003 Jan 15;63(2):304-7. PMID:12543779
- ↑ French CA, Miyoshi I, Aster JC, Kubonishi I, Kroll TG, Dal Cin P, Vargas SO, Perez-Atayde AR, Fletcher JA. BRD4 bromodomain gene rearrangement in aggressive carcinoma with translocation t(15;19). Am J Pathol. 2001 Dec;159(6):1987-92. PMID:11733348 doi:10.1016/S0002-9440(10)63049-0
- ↑ Allen BK, Mehta S, Ember SWJ, Zhu JY, Schonbrunn E, Ayad NG, Schurer SC. Identification of a Novel Class of BRD4 Inhibitors by Computational Screening and Binding Simulations. ACS Omega. 2017 Aug 31;2(8):4760-4771. doi: 10.1021/acsomega.7b00553. Epub 2017, Aug 21. PMID:28884163 doi:http://dx.doi.org/10.1021/acsomega.7b00553
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