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==BRD4 second bromodomain (BD2) in complex with dual PI3 kinase (PI3K) inhibitor SF2558HA==
==BRD4 second bromodomain (BD2) in complex with dual PI3 kinase (PI3K) inhibitor SF2558HA==
<StructureSection load='5u2c' size='340' side='right' caption='[[5u2c]], [[Resolution|resolution]] 3.30&Aring;' scene=''>
<StructureSection load='5u2c' size='340' side='right'caption='[[5u2c]], [[Resolution|resolution]] 3.30&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[5u2c]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5U2C OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5U2C FirstGlance]. <br>
<table><tr><td colspan='2'>[[5u2c]] 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=5U2C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5U2C FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=82Y:N-HYDROXY-4-[5-(MORPHOLIN-4-YL)-7-OXO-7H-THIENO[3,2-B]PYRAN-3-YL]BENZAMIDE'>82Y</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]] 3.3&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5u28|5u28]], [[5u2f|5u2f]], [[5u2e|5u2e]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=82Y:N-HYDROXY-4-[5-(MORPHOLIN-4-YL)-7-OXO-7H-THIENO[3,2-B]PYRAN-3-YL]BENZAMIDE'>82Y</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=5u2c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5u2c OCA], [http://pdbe.org/5u2c PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5u2c RCSB], [http://www.ebi.ac.uk/pdbsum/5u2c PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5u2c 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=5u2c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5u2c OCA], [https://pdbe.org/5u2c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5u2c RCSB], [https://www.ebi.ac.uk/pdbsum/5u2c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5u2c 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 ==
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<ref>PMID:28137841</ref>
==See Also==
 
*[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]]
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5u2c" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Andrews, F H]]
[[Category: Homo sapiens]]
[[Category: Kutateladze, T G]]
[[Category: Large Structures]]
[[Category: Bromodomain]]
[[Category: Andrews FH]]
[[Category: Epigenetic]]
[[Category: Kutateladze TG]]
[[Category: Inhibitor]]
[[Category: Transcription]]
[[Category: Transcription regulator-inhibitor complex]]

Latest revision as of 17:24, 6 March 2024

BRD4 second bromodomain (BD2) in complex with dual PI3 kinase (PI3K) inhibitor SF2558HABRD4 second bromodomain (BD2) in complex with dual PI3 kinase (PI3K) inhibitor SF2558HA

Structural highlights

5u2c is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.3Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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).

See Also

References

  1. ↑ 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
  2. ↑ 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

5u2c, resolution 3.30Å

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