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| | <StructureSection load='5u28' size='340' side='right'caption='[[5u28]], [[Resolution|resolution]] 1.80Å' scene=''> | | <StructureSection load='5u28' size='340' side='right'caption='[[5u28]], [[Resolution|resolution]] 1.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5u28]] 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=5U28 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5U28 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5u28]] 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=5U28 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5U28 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=82V:3-(2,3-DIHYDRO-1,4-BENZODIOXIN-6-YL)-5-(MORPHOLIN-4-YL)-7H-THIENO[3,2-B]PYRAN-7-ONE'>82V</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=SCN:THIOCYANATE+ION'>SCN</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]] 1.798Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5u2f|5u2f]], [[5u2c|5u2c]], [[5u2e|5u2e]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=82V:3-(2,3-DIHYDRO-1,4-BENZODIOXIN-6-YL)-5-(MORPHOLIN-4-YL)-7H-THIENO[3,2-B]PYRAN-7-ONE'>82V</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=SCN:THIOCYANATE+ION'>SCN</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=5u28 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5u28 OCA], [https://pdbe.org/5u28 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5u28 RCSB], [https://www.ebi.ac.uk/pdbsum/5u28 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5u28 ProSAT]</span></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=5u28 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5u28 OCA], [http://pdbe.org/5u28 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5u28 RCSB], [http://www.ebi.ac.uk/pdbsum/5u28 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5u28 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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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Andrews, F H]] | + | [[Category: Andrews FH]] |
| - | [[Category: Kutateladze, T G]] | + | [[Category: Kutateladze TG]] |
| - | [[Category: Bromodomain]]
| + | |
| - | [[Category: Epigenetic]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Transcription]]
| + | |
| - | [[Category: Transcription regulator-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
MYC is a major cancer driver but is documented to be a difficult therapeutic target itself. Here, we report on the biological activity, the structural basis, and therapeutic effects of the family of multitargeted compounds that simultaneously disrupt functions of two critical MYC-mediating factors through inhibiting the acetyllysine binding of BRD4 and the kinase activity of PI3K. We show that the dual-action inhibitor impairs PI3K/BRD4 signaling in vitro and in vivo and affords maximal MYC down-regulation. The concomitant inhibition of PI3K and BRD4 blocks MYC expression and activation, promotes MYC degradation, and markedly inhibits cancer cell growth and metastasis. Collectively, our findings suggest that the dual-activity inhibitor represents a highly promising lead compound for the development of novel anticancer therapeutics.
Dual-activity PI3K-BRD4 inhibitor for the orthogonal inhibition of MYC to block tumor growth and metastasis.,Andrews FH, Singh AR, Joshi S, Smith CA, Morales GA, Garlich JR, Durden DL, Kutateladze TG Proc Natl Acad Sci U S A. 2017 Feb 14;114(7):E1072-E1080. doi:, 10.1073/pnas.1613091114. Epub 2017 Jan 30. PMID:28137841[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
- ↑ Andrews FH, Singh AR, Joshi S, Smith CA, Morales GA, Garlich JR, Durden DL, Kutateladze TG. Dual-activity PI3K-BRD4 inhibitor for the orthogonal inhibition of MYC to block tumor growth and metastasis. Proc Natl Acad Sci U S A. 2017 Feb 14;114(7):E1072-E1080. doi:, 10.1073/pnas.1613091114. Epub 2017 Jan 30. PMID:28137841 doi:http://dx.doi.org/10.1073/pnas.1613091114
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