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{{STRUCTURE_4mep|  PDB=4mep  |  SCENE=  }}
===Crystal Structure of the first bromodomain of human BRD4 in complex with a 3-chloro-pyridone ligand===
{{ABSTRACT_PUBMED_24090311}}


==Disease==
==Crystal Structure of the first bromodomain of human BRD4 in complex with a 3-chloro-pyridone ligand==
<StructureSection load='4mep' size='340' side='right' caption='[[4mep]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4mep]] 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=4MEP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4MEP FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=24Y:3-CHLORO-5-[1-(3-METHYLPYRIDIN-2-YL)-3-PHENYL-1H-1,2,4-TRIAZOL-5-YL]PYRIDIN-2(1H)-ONE'>24Y</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4men|4men]], [[4meo|4meo]], [[4meq|4meq]]</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=4mep FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mep OCA], [http://pdbe.org/4mep PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4mep RCSB], [http://www.ebi.ac.uk/pdbsum/4mep PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4mep 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>   
[[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>   
== Function ==
[[http://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 ==
Bromodomains (BRDs) are epigenetic readers that recognize acetylated-lysine (KAc) on proteins and are implicated in a number of diseases. We describe a virtual screening approach to identify BRD inhibitors. Key elements of this approach are the extensive design and use of substructure queries to compile a set of commercially available compounds featuring novel putative KAc mimetics and docking this set for final compound selection. We describe the validation of this approach by applying it to the first BRD of BRD4. The selection and testing of 143 compounds lead to the discovery of six novel hits, including four unprecedented KAc mimetics. We solved the crystal structure of four hits, determined their binding mode, and improved their potency through synthesis and the purchase of derivatives. This work provides a validated virtual screening approach that is applicable to other BRDs and describes novel KAc mimetics that can be further explored to design more potent inhibitors.


==Function==
Discovery of Novel Small-Molecule Inhibitors of BRD4 Using Structure-Based Virtual Screening.,Vidler LR, Filippakopoulos P, Fedorov O, Picaud S, Martin S, Tomsett M, Woodward H, Brown N, Knapp S, Hoelder S J Med Chem. 2013 Oct 3. PMID:24090311<ref>PMID:24090311</ref>
[[http://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[4mep]] 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=4MEP OCA].
</div>
<div class="pdbe-citations 4mep" style="background-color:#fffaf0;"></div>


==Reference==
==See Also==
<ref group="xtra">PMID:024090311</ref><references group="xtra"/><references/>
*[[Bromodomain-containing protein|Bromodomain-containing protein]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Human]]
[[Category: Arrowsmith, C H.]]
[[Category: Arrowsmith, C H]]
[[Category: Bountra, C.]]
[[Category: Bountra, C]]
[[Category: Brown, N.]]
[[Category: Brown, N]]
[[Category: Delft, F von.]]
[[Category: Delft, F von]]
[[Category: Edwards, A M.]]
[[Category: Edwards, A M]]
[[Category: Fedorov, O.]]
[[Category: Fedorov, O]]
[[Category: Felletar, I.]]
[[Category: Felletar, I]]
[[Category: Filippakopoulos, P.]]
[[Category: Filippakopoulos, P]]
[[Category: Hoelder, S.]]
[[Category: Hoelder, S]]
[[Category: Knapp, S.]]
[[Category: Knapp, S]]
[[Category: Martin, S.]]
[[Category: Martin, S]]
[[Category: Picaud, S.]]
[[Category: Picaud, S]]
[[Category: SGC, Structural Genomics Consortium.]]
[[Category: Structural genomic]]
[[Category: Vidler, L R.]]
[[Category: Vidler, L R]]
[[Category: Weigelt, J.]]
[[Category: Weigelt, J]]
[[Category: Brd]]
[[Category: Brd]]
[[Category: Brd4]]
[[Category: Brd4]]
Line 38: Line 53:
[[Category: Sgc]]
[[Category: Sgc]]
[[Category: Small molecule inhibitor]]
[[Category: Small molecule inhibitor]]
[[Category: Structural genomics consortium]]
[[Category: Transcription-transcription inhibitor complex]]
[[Category: Transcription-transcription inhibitor complex]]

Revision as of 04:39, 5 August 2016

Crystal Structure of the first bromodomain of human BRD4 in complex with a 3-chloro-pyridone ligandCrystal Structure of the first bromodomain of human BRD4 in complex with a 3-chloro-pyridone ligand

Structural highlights

4mep is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:BRD4, HUNK1 (HUMAN)
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

Bromodomains (BRDs) are epigenetic readers that recognize acetylated-lysine (KAc) on proteins and are implicated in a number of diseases. We describe a virtual screening approach to identify BRD inhibitors. Key elements of this approach are the extensive design and use of substructure queries to compile a set of commercially available compounds featuring novel putative KAc mimetics and docking this set for final compound selection. We describe the validation of this approach by applying it to the first BRD of BRD4. The selection and testing of 143 compounds lead to the discovery of six novel hits, including four unprecedented KAc mimetics. We solved the crystal structure of four hits, determined their binding mode, and improved their potency through synthesis and the purchase of derivatives. This work provides a validated virtual screening approach that is applicable to other BRDs and describes novel KAc mimetics that can be further explored to design more potent inhibitors.

Discovery of Novel Small-Molecule Inhibitors of BRD4 Using Structure-Based Virtual Screening.,Vidler LR, Filippakopoulos P, Fedorov O, Picaud S, Martin S, Tomsett M, Woodward H, Brown N, Knapp S, Hoelder S J Med Chem. 2013 Oct 3. PMID:24090311[3]

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

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
  3. ↑ Vidler LR, Filippakopoulos P, Fedorov O, Picaud S, Martin S, Tomsett M, Woodward H, Brown N, Knapp S, Hoelder S. Discovery of Novel Small-Molecule Inhibitors of BRD4 Using Structure-Based Virtual Screening. J Med Chem. 2013 Oct 3. PMID:24090311 doi:http://dx.doi.org/10.1021/jm4011302

4mep, resolution 1.85Å

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