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==Crystal Structure of the first bromodomain of human BRD4 in complex with a 3-chloro-pyridone ligand== | ==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]] 1.85Å' scene=''> | <StructureSection load='4mep' size='340' side='right'caption='[[4mep]], [[Resolution|resolution]] 1.85Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4mep]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[4mep]] 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=4MEP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4mep FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mep OCA], [https://pdbe.org/4mep PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4mep RCSB], [https://www.ebi.ac.uk/pdbsum/4mep PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4mep ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Disease == | == Disease == | ||
[ | [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 == | ||
[ | [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 == | ||
| Line 24: | Line 22: | ||
==See Also== | ==See Also== | ||
*[[Bromodomain-containing protein|Bromodomain-containing protein]] | *[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Arrowsmith CH]] | ||
[[Category: | [[Category: Bountra C]] | ||
[[Category: | [[Category: Brown N]] | ||
[[Category: Edwards | [[Category: Edwards AM]] | ||
[[Category: Fedorov | [[Category: Fedorov O]] | ||
[[Category: Felletar | [[Category: Felletar I]] | ||
[[Category: Filippakopoulos | [[Category: Filippakopoulos P]] | ||
[[Category: Hoelder | [[Category: Hoelder S]] | ||
[[Category: Knapp | [[Category: Knapp S]] | ||
[[Category: Martin | [[Category: Martin S]] | ||
[[Category: Picaud | [[Category: Picaud S]] | ||
[[Category: Vidler LR]] | |||
[[Category: Vidler | [[Category: Weigelt J]] | ||
[[Category: Weigelt | [[Category: Von Delft F]] | ||
[[Category: | |||
Revision as of 14:12, 21 December 2022
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
DiseaseBRD4_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] FunctionBRD4_HUMAN Plays a role in a process governing chromosomal dynamics during mitosis (By similarity). Publication Abstract from PubMedBromodomains (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 AlsoReferences
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