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4j0s

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Revision as of 21:22, 16 November 2022

Crystal Structure of the first bromodomain of human BRD4 in complex with a 3,5-dimethylisoxazol ligand

Structural highlights

4j0s is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
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

The bromodomain protein module, which binds to acetylated lysine, is emerging as an important epigenetic therapeutic target. We report the structure-guided optimization of 3,5-dimethylisoxazole derivatives to develop potent inhibitors of the BET (bromodomain and extra terminal domain) bromodomain family with good ligand efficiency. X-ray crystal structures of the most potent compounds reveal key interactions required for high affinity at BRD4(1). Cellular studies demonstrate that the phenol and acetate derivatives of the lead compounds showed strong antiproliferative effects on MV4;11 acute myeloid leukemia cells, as shown for other BET bromodomain inhibitors and genetic BRD4 knockdown, whereas the reported compounds showed no general cytotoxicity in other cancer cell lines tested.

Optimization of 3,5-dimethylisoxazole derivatives as potent bromodomain ligands.,Hewings DS, Fedorov O, Filippakopoulos P, Martin S, Picaud S, Tumber A, Wells C, Olcina MM, Freeman K, Gill A, Ritchie AJ, Sheppard DW, Russell AJ, Hammond EM, Knapp S, Brennan PE, Conway SJ J Med Chem. 2013 Apr 25;56(8):3217-27. doi: 10.1021/jm301588r. Epub 2013 Apr 5. PMID:23517011^[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
↑ Hewings DS, Fedorov O, Filippakopoulos P, Martin S, Picaud S, Tumber A, Wells C, Olcina MM, Freeman K, Gill A, Ritchie AJ, Sheppard DW, Russell AJ, Hammond EM, Knapp S, Brennan PE, Conway SJ. Optimization of 3,5-dimethylisoxazole derivatives as potent bromodomain ligands. J Med Chem. 2013 Apr 25;56(8):3217-27. doi: 10.1021/jm301588r. Epub 2013 Apr 5. PMID:23517011 doi:10.1021/jm301588r

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/4j0s"

@@ Line 1: / Line 1: @@
 ==Crystal Structure of the first bromodomain of human BRD4 in complex with a 3,5-dimethylisoxazol ligand==
-<StructureSection load='4j0s' size='340' side='right' caption='[[4j0s]], [[Resolution|resolution]] 1.84&Aring;' scene=''>
+<StructureSection load='4j0s' size='340' side='right'caption='[[4j0s]], [[Resolution|resolution]] 1.84&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4j0s]] 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=4J0S OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4J0S FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4j0s]] 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=4J0S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4J0S FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1H3:3-(3,5-DIMETHYL-1,2-OXAZOL-4-YL)-5-[(S)-HYDROXY(PHENYL)METHYL]PHENOL'>1H3</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1H3:3-(3,5-DIMETHYL-1,2-OXAZOL-4-YL)-5-[(S)-HYDROXY(PHENYL)METHYL]PHENOL'>1H3</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4j0r|4j0r]]</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=4j0s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4j0s OCA], [https://pdbe.org/4j0s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4j0s RCSB], [https://www.ebi.ac.uk/pdbsum/4j0s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4j0s 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=4j0s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4j0s OCA], [http://pdbe.org/4j0s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4j0s RCSB], [http://www.ebi.ac.uk/pdbsum/4j0s PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4j0s 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 24: / Line 22: @@
 ==See Also==
-*[[Bromodomain-containing protein|Bromodomain-containing protein]]
+*[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
-[[Category: Arrowsmith, C H]]
+[[Category: Large Structures]]
-[[Category: Bountra, C]]
+[[Category: Arrowsmith CH]]
-[[Category: Conway, S J]]
+[[Category: Bountra C]]
-[[Category: Delft, F von]]
+[[Category: Conway SJ]]
-[[Category: Edwards, A]]
+[[Category: Edwards A]]
-[[Category: Felletar, I]]
+[[Category: Felletar I]]
-[[Category: Filippakopoulos, P]]
+[[Category: Filippakopoulos P]]
-[[Category: Hewings, D S]]
+[[Category: Hewings DS]]
-[[Category: Knapp, S]]
+[[Category: Knapp S]]
-[[Category: Picaud, S]]
+[[Category: Picaud S]]
-[[Category: Qi, J]]
+[[Category: Qi J]]
-[[Category: Structural genomic]]
+[[Category: Von Delft F]]
-[[Category: Brd4]]
-[[Category: Bromodomain containing protein 4]]
-[[Category: Cap]]
-[[Category: Hunk1]]
-[[Category: Isoxazole]]
-[[Category: Mcap]]
-[[Category: Mitotic chromosome associated protein]]
-[[Category: Sgc]]
-[[Category: Signaling protein]]

4j0s

From Proteopedia

Revision as of 21:22, 16 November 2022

Crystal Structure of the first bromodomain of human BRD4 in complex with a 3,5-dimethylisoxazol ligand

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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