View source for 7rxt


==Crystal of BRD4(D1) with 2-[(3R)-3-{5-[2-(3,5-dimethylphenoxy)pyrimidin-4-yl]-4-(4-iodophenyl)-1H-imidazol-1-yl}pyrrolidin-1-yl]ethan-1-amine==
<StructureSection load='7rxt' size='340' side='right'caption='[[7rxt]], [[Resolution|resolution]] 1.68&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7rxt]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7RXT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RXT FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7ZK:2-[(3R)-3-{5-[2-(3,5-dimethylphenoxy)pyrimidin-4-yl]-4-(4-iodophenyl)-1H-imidazol-1-yl}pyrrolidin-1-yl]ethan-1-amine'>7ZK</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=7rxt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rxt OCA], [https://pdbe.org/7rxt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rxt RCSB], [https://www.ebi.ac.uk/pdbsum/7rxt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rxt ProSAT]</span></td></tr>
</table>
== 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 ==
[[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 ==
Chemical probes for epigenetic proteins are essential tools for dissecting the molecular mechanisms for gene regulation and therapeutic development. The bromodomain and extra-terminal (BET) proteins are master transcriptional regulators. Despite promising therapeutic targets, selective small molecule inhibitors for a single bromodomain remain an unmet goal due to their high sequence similarity. Here, we address this challenge via a structure-activity relationship study using 1,4,5-trisubstituted imidazoles against the BRD4 N-terminal bromodomain (D1). Leading compounds 26 and 30 have 15 and 18 nM affinity against BRD4 D1 and over 500-fold selectivity against BRD2 D1 and BRD4 D2 via ITC. Broader BET selectivity was confirmed by fluorescence anisotropy, thermal shift, and CETSA. Despite BRD4 engagement, BRD4 D1 inhibition was unable to reduce c-Myc expression at low concentration in multiple myeloma cells. Conversely, for inflammation, IL-8 and chemokine downregulation were observed. These results provide new design rules for selective inhibitors of an individual BET bromodomain.

A Structure-based Design Approach for Generating High Affinity BRD4 D1-Selective Chemical Probes.,Cui H, Divakaran A, Hoell ZJ, Ellingson MO, Scholtz CR, Zahid H, Johnson JA, Griffith EC, Gee CT, Lee AL, Khanal S, Shi K, Aihara H, Shah VH, Lee RE, Harki DA, Pomerantz WCK J Med Chem. 2022 Jan 10. doi: 10.1021/acs.jmedchem.1c01779. PMID:35007061<ref>PMID:35007061</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7rxt" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Aihara, H]]
[[Category: Cui, H]]
[[Category: Johnson, J A]]
[[Category: Pomerantz, W C.K]]
[[Category: Shi, K]]
[[Category: Brd4]]
[[Category: Gene regulation]]
[[Category: Gene regulation-inhibitor complex]]