4ogj: Difference between revisions
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==Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor TG-101348== | ==Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor TG-101348== | ||
<StructureSection load='4ogj' size='340' side='right' caption='[[4ogj]], [[Resolution|resolution]] 1.65Å' scene=''> | <StructureSection load='4ogj' size='340' side='right'caption='[[4ogj]], [[Resolution|resolution]] 1.65Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4ogj]] is a 2 chain structure with sequence from [ | <table><tr><td colspan='2'>[[4ogj]] 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=4OGJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4OGJ FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2TA:N-TERT-BUTYL-3-{[5-METHYL-2-({4-[2-(PYRROLIDIN-1-YL)ETHOXY]PHENYL}AMINO)PYRIMIDIN-4-YL]AMINO}BENZENESULFONAMIDE'>2TA</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.65Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2TA:N-TERT-BUTYL-3-{[5-METHYL-2-({4-[2-(PYRROLIDIN-1-YL)ETHOXY]PHENYL}AMINO)PYRIMIDIN-4-YL]AMINO}BENZENESULFONAMIDE'>2TA</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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=4ogj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ogj OCA], [https://pdbe.org/4ogj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ogj RCSB], [https://www.ebi.ac.uk/pdbsum/4ogj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ogj 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 23: | ||
==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: Edwards | [[Category: Edwards AM]] | ||
[[Category: Fedorov | [[Category: Fedorov O]] | ||
[[Category: Filippakopoulos | [[Category: Filippakopoulos P]] | ||
[[Category: Jose | [[Category: Jose B]] | ||
[[Category: Knapp | [[Category: Knapp S]] | ||
[[Category: Martin | [[Category: Martin S]] | ||
[[Category: Picaud | [[Category: Picaud S]] | ||
[[Category: | [[Category: Von Delft F]] | ||
Latest revision as of 20:13, 20 September 2023
Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor TG-101348Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor TG-101348
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 PubMedConcomitant inhibition of multiple cancer-driving kinases is an established strategy to improve the durability of clinical responses to targeted therapies. The difficulty of discovering kinase inhibitors with an appropriate multitarget profile has, however, necessitated the application of combination therapies, which can pose major clinical development challenges. Epigenetic reader domains of the bromodomain family have recently emerged as new targets for cancer therapy. Here we report that several clinical kinase inhibitors also inhibit bromodomains with therapeutically relevant potencies and are best classified as dual kinase-bromodomain inhibitors. Nanomolar activity on BRD4 by BI-2536 and TG-101348, which are clinical PLK1 and JAK2-FLT3 kinase inhibitors, respectively, is particularly noteworthy as these combinations of activities on independent oncogenic pathways exemplify a new strategy for rational single-agent polypharmacological targeting. Furthermore, structure-activity relationships and co-crystal structures identify design features that enable a general platform for the rational design of dual kinase-bromodomain inhibitors. Dual kinase-bromodomain inhibitors for rationally designed polypharmacology.,Ciceri P, Muller S, O'Mahony A, Fedorov O, Filippakopoulos P, Hunt JP, Lasater EA, Pallares G, Picaud S, Wells C, Martin S, Wodicka LM, Shah NP, Treiber DK, Knapp S Nat Chem Biol. 2014 Apr;10(4):305-12. doi: 10.1038/nchembio.1471. Epub 2014 Mar, 2. PMID:24584101[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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