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| | ==Selective pharmacological inhibition of the CREB binding protein bromodomain regulates inflammatory cytokines in macrophages and RGS4 in neurons== | | ==Selective pharmacological inhibition of the CREB binding protein bromodomain regulates inflammatory cytokines in macrophages and RGS4 in neurons== |
| - | <StructureSection load='5cfw' size='340' side='right' caption='[[5cfw]], [[Resolution|resolution]] 1.15Å' scene=''> | + | <StructureSection load='5cfw' size='340' side='right'caption='[[5cfw]], [[Resolution|resolution]] 1.15Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5cfw]] 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=5CFW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5CFW FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5cfw]] 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=5CFW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5CFW FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=53W:5-(3,5-DIMETHYL-1,2-OXAZOL-4-YL)-2-[2-(4-METHOXYPHENYL)ETHYL]-1-[2-(MORPHOLIN-4-YL)ETHYL]-1H-BENZIMIDAZOLE'>53W</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=53W:5-(3,5-DIMETHYL-1,2-OXAZOL-4-YL)-2-[2-(4-METHOXYPHENYL)ETHYL]-1-[2-(MORPHOLIN-4-YL)ETHYL]-1H-BENZIMIDAZOLE'>53W</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5cgp|5cgp]]</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=5cfw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cfw OCA], [https://pdbe.org/5cfw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5cfw RCSB], [https://www.ebi.ac.uk/pdbsum/5cfw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5cfw ProSAT]</span></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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5cfw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cfw OCA], [http://pdbe.org/5cfw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5cfw RCSB], [http://www.ebi.ac.uk/pdbsum/5cfw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5cfw 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 5cfw" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5cfw" 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: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Chekler, E L]] | + | [[Category: Large Structures]] |
| - | [[Category: Jones, L H]] | + | [[Category: Chekler EL]] |
| - | [[Category: Inhibitor complex]] | + | [[Category: Jones LH]] |
| - | [[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
Bromodomains are involved in transcriptional regulation through the recognition of acetyl lysine modifications on diverse proteins. Selective pharmacological modulators of bromodomains are lacking, although the largely hydrophobic nature of the pocket makes these modules attractive targets for small-molecule inhibitors. This work describes the structure-based design of a highly selective inhibitor of the CREB binding protein (CBP) bromodomain and its use in cell-based transcriptional profiling experiments. The inhibitor downregulated a number of inflammatory genes in macrophages that were not affected by a selective BET bromodomain inhibitor. In addition, the CBP bromodomain inhibitor modulated the mRNA level of the regulator of G-protein signaling 4 (RGS4) gene in neurons, suggesting a potential therapeutic opportunity for CBP inhibitors in the treatment of neurological disorders.
Transcriptional Profiling of a Selective CREB Binding Protein Bromodomain Inhibitor Highlights Therapeutic Opportunities.,Chekler EL, Pellegrino JA, Lanz TA, Denny RA, Flick AC, Coe J, Langille J, Basak A, Liu S, Stock IA, Sahasrabudhe P, Bonin PD, Lee K, Pletcher MT, Jones LH Chem Biol. 2015 Dec 17;22(12):1588-96. doi: 10.1016/j.chembiol.2015.10.013. Epub , 2015 Dec 3. PMID:26670081[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
- ↑ Chekler EL, Pellegrino JA, Lanz TA, Denny RA, Flick AC, Coe J, Langille J, Basak A, Liu S, Stock IA, Sahasrabudhe P, Bonin PD, Lee K, Pletcher MT, Jones LH. Transcriptional Profiling of a Selective CREB Binding Protein Bromodomain Inhibitor Highlights Therapeutic Opportunities. Chem Biol. 2015 Dec 17;22(12):1588-96. doi: 10.1016/j.chembiol.2015.10.013. Epub , 2015 Dec 3. PMID:26670081 doi:http://dx.doi.org/10.1016/j.chembiol.2015.10.013
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