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6mh7

From Proteopedia

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Crystal structure of the first bromodomain of human BRD4 in complex with SKT-68, a 1,4,5-trisubstituted imidazole analogue

Structural highlights

6mh7 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 1.74Å
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).

Publication Abstract from PubMed

As regulators of transcription, epigenetic proteins that interpret post-translational modifications to N-terminal histone tails are essential for maintaining cellular homeostasis. When dysregulated, "reader" proteins become drivers of disease. In the case of bromodomains, which recognize N-epsilon-acetylated lysine, selective inhibition of individual bromodomain-and-extra-terminal (BET)-family bromodomains has proven challenging. We describe the >55-fold N-terminal-BET bromodomain selectivity of 1,4,5-trisubstituted-imidazole dual kinase-bromodomain inhibitors. Selectivity for the BRD4 N-terminal bromodomain (BRD4(1)) over its second bromodomain (BRD4(2)) arises from the displacement of ordered waters and the conformational flexibility of lysine-141 in BRD4(1). Cellular efficacy was demonstrated via reduction of c-Myc expression, inhibition of NF-kappaB signaling, and suppression of IL-8 production through potential synergistic inhibition of BRD4(1) and p38alpha. These dual inhibitors provide a new scaffold for domain-selective inhibition of BRD4, the aberrant function of which plays a key role in cancer and inflammatory signaling.

Molecular Basis for the N-Terminal Bromodomain-and-Extra-Terminal-Family Selectivity of a Dual Kinase-Bromodomain Inhibitor.,Divakaran A, Talluri SK, Ayoub AM, Mishra NK, Cui H, Widen JC, Berndt N, Zhu JY, Carlson AS, Topczewski JJ, Schonbrunn EK, Harki DA, Pomerantz WCK J Med Chem. 2018 Oct 25;61(20):9316-9334. doi: 10.1021/acs.jmedchem.8b01248. Epub, 2018 Oct 16. PMID:30253095^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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
↑ Divakaran A, Talluri SK, Ayoub AM, Mishra NK, Cui H, Widen JC, Berndt N, Zhu JY, Carlson AS, Topczewski JJ, Schonbrunn EK, Harki DA, Pomerantz WCK. Molecular Basis for the N-Terminal Bromodomain-and-Extra-Terminal-Family Selectivity of a Dual Kinase-Bromodomain Inhibitor. J Med Chem. 2018 Oct 25;61(20):9316-9334. doi: 10.1021/acs.jmedchem.8b01248. Epub, 2018 Oct 16. PMID:30253095 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b01248

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6mh7"

Categories: Homo sapiens | Large Structures | Schonbrunn E | Zhu J-Y

@@ Line 3: / Line 3: @@
 <StructureSection load='6mh7' size='340' side='right'caption='[[6mh7]], [[Resolution|resolution]] 1.74&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6mh7]] 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=6MH7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MH7 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6mh7]] 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=6MH7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6MH7 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=JQY:N-(3,4-dimethylphenyl)-4-[4-(4-fluorophenyl)-1-(piperidin-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine'>JQY</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]] 1.74&#8491;</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=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=JQY:N-(3,4-dimethylphenyl)-4-[4-(4-fluorophenyl)-1-(piperidin-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine'>JQY</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=6mh7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mh7 OCA], [http://pdbe.org/6mh7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6mh7 RCSB], [http://www.ebi.ac.uk/pdbsum/6mh7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6mh7 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=6mh7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mh7 OCA], [https://pdbe.org/6mh7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6mh7 RCSB], [https://www.ebi.ac.uk/pdbsum/6mh7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6mh7 ProSAT]</span></td></tr>
 </table>
 == 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 ==
-[[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 ==
@@ Line 21: / Line 21: @@
 </div>
 <div class="pdbe-citations 6mh7" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Schonbrunn, E]]
+[[Category: Schonbrunn E]]
-[[Category: Zhu, J Y]]
+[[Category: Zhu J-Y]]
-[[Category: 19f-nmr]]
-[[Category: Bromodomain]]
-[[Category: Cap]]
-[[Category: Hunk1]]
-[[Category: Inflammation]]
-[[Category: Inhibitor]]
-[[Category: Map-kinase inhibition]]
-[[Category: Mcap]]
-[[Category: Protein binding-inhibitor complex]]
-[[Category: Transcription-inhibitor complex]]

6mh7

From Proteopedia

Current revision

Crystal structure of the first bromodomain of human BRD4 in complex with SKT-68, a 1,4,5-trisubstituted imidazole analogue

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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