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| <StructureSection load='5ula' size='340' side='right'caption='[[5ula]], [[Resolution|resolution]] 1.50Å' scene=''> | | <StructureSection load='5ula' size='340' side='right'caption='[[5ula]], [[Resolution|resolution]] 1.50Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[5ula]] 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=5ULA OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5ULA FirstGlance]. <br> | | <table><tr><td colspan='2'>[[5ula]] 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=5ULA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ULA FirstGlance]. <br> |
| </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5MJ:3-CHLORANYL-~{N}-(4-METHOXYPHENYL)-4-[(2-METHYL-3-OXIDANYLIDENE-CYCLOPENTEN-1-YL)AMINO]BENZAMIDE'>5MJ</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]] 1.5Å</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=5MJ:3-CHLORANYL-~{N}-(4-METHOXYPHENYL)-4-[(2-METHYL-3-OXIDANYLIDENE-CYCLOPENTEN-1-YL)AMINO]BENZAMIDE'>5MJ</scene></td></tr> |
| <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5ula FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ula OCA], [http://pdbe.org/5ula PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ula RCSB], [http://www.ebi.ac.uk/pdbsum/5ula PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ula 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=5ula FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ula OCA], [https://pdbe.org/5ula PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ula RCSB], [https://www.ebi.ac.uk/pdbsum/5ula PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ula 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;">
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| == Publication Abstract from PubMed ==
| |
| T-helper 17 (Th17) cells have important functions in adaptor immunity and have also been implicated in inflammatory disorders. The bromodomain and extraterminal domain (BET) family proteins regulate gene transcription during lineage-specific differentiation of naive CD4+ T cells to produce mature T-helper cells. Inhibition of acetyl-lysine binding of the BET proteins by pan-BET bromodomain (BrD) inhibitors, such as JQ1, broadly affects differentiation of Th17, Th1, and Th2 cells that have distinct immune functions, thus limiting their therapeutic potential. Whether these BET proteins represent viable new epigenetic drug targets for inflammatory disorders has remained an unanswered question. In this study, we report that selective inhibition of the first bromodomain of BET proteins with our newly designed small molecule MS402 inhibits primarily Th17 cell differentiation with a little or almost no effect on Th1 or Th2 and Treg cells. MS402 preferentially renders Brd4 binding to Th17 signature gene loci over those of housekeeping genes and reduces Brd4 recruitment of p-TEFb to phosphorylate and activate RNA polymerase II for transcription elongation. We further show that MS402 prevents and ameliorates T-cell transfer-induced colitis in mice by blocking Th17 cell overdevelopment. Thus, selective pharmacological modulation of individual bromodomains likely represents a strategy for treatment of inflammatory bowel diseases.
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| BET N-terminal bromodomain inhibition selectively blocks Th17 cell differentiation and ameliorates colitis in mice.,Cheung K, Lu G, Sharma R, Vincek A, Zhang R, Plotnikov AN, Zhang F, Zhang Q, Ju Y, Hu Y, Zhao L, Han X, Meslamani J, Xu F, Jaganathan A, Shen T, Zhu H, Rusinova E, Zeng L, Zhou J, Yang J, Peng L, Ohlmeyer M, Walsh MJ, Zhang DY, Xiong H, Zhou MM Proc Natl Acad Sci U S A. 2017 Mar 14;114(11):2952-2957. doi:, 10.1073/pnas.1615601114. Epub 2017 Mar 6. PMID:28265070<ref>PMID:28265070</ref>
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| From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| </div>
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| <div class="pdbe-citations 5ula" 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: Joshua, j]] | | [[Category: Joshua j]] |
| [[Category: Plotnikov, A N]] | | [[Category: Plotnikov AN]] |
| [[Category: Zhou, M M]] | | [[Category: Zhou M-M]] |
| [[Category: Bromodomain]]
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| [[Category: Inhibitor]]
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| [[Category: Transcription]]
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| [[Category: Transcription-inhibitor complex]]
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