View source for 9iv5


==BRD4 in complex with compound7==
<StructureSection load='9iv5' size='340' side='right'caption='[[9iv5]], [[Resolution|resolution]] 1.59&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9iv5]] 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=9IV5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9IV5 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.59&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1D95:7-[2-fluoranyl-5-(oxetan-3-ylmethoxy)-3-(1,3,5-trimethylpyrazol-4-yl)phenyl]-1~{H}-imidazo[4,5-b]pyridine'>A1D95</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</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=9iv5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9iv5 OCA], [https://pdbe.org/9iv5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9iv5 RCSB], [https://www.ebi.ac.uk/pdbsum/9iv5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9iv5 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 ==
Rational design of bromodomain (BD)-selective inhibitors could mitigate on-target toxicities associated with pan-BET inhibition but is challenging despite the availability of high-resolution structures. By simultaneously forming water bridges with BD1-specific residues in both the BC ring and the ZA channel, we identified a potent and orally bioavailable BET BD1-selective inhibitor DDO-8958, which exhibited a K(D) of 5.6 nM for BRD4 BD1 and a 214-fold selectivity for BRD4 BD1 over BD2. The cocrystal structure demonstrated a unique multi-water bridge mechanism involving BD1-specific residues K91- and D145-driven BD1 selectivity. DDO-8958 extensively influenced the oncogene expression and metabolic pathway, including oxidative phosphorylation in MIA PaCa-2. In vivo, DDO-8958 inhibited tumor growth and markedly augmented the therapeutic efficacy of the glycolysis inhibitor 2-DG. These findings illuminate that multi-water bridges enable design of BD1-selective inhibitors and a therapeutic strategy involving combined targeting of BD1-induced epigenetic reprogramming and glycolysis pathways for the management of pancreatic cancer.

Multi-Water Bridges Enable Design of BET BD1-Selective Inhibitors for Pancreatic Cancer Therapy.,Chen X, Kang W, Wu T, Cao D, Chen Y, Du Z, Yan L, Meng F, Wang X, You Q, Xiong B, Guo X, Jiang Z J Med Chem. 2025 Mar 13;68(5):5719-5735. doi: 10.1021/acs.jmedchem.4c03069. Epub , 2025 Feb 26. PMID:40011026<ref>PMID:40011026</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9iv5" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Cao D]]
[[Category: Chen X]]
[[Category: Du Z]]
[[Category: Jiang Z]]
[[Category: Xiong B]]