6wgx
From Proteopedia
(Difference between revisions)
| Line 1: | Line 1: | ||
==Cocrystal of BRD4(D1) with a selective inhibitor== | ==Cocrystal of BRD4(D1) with a selective inhibitor== | ||
| - | <StructureSection load='6wgx' size='340' side='right'caption='[[6wgx]]' scene=''> | + | <StructureSection load='6wgx' size='340' side='right'caption='[[6wgx]], [[Resolution|resolution]] 1.53Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6WGX OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6WGX FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6wgx]] is a 2 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=6WGX OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6WGX FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6wgx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6wgx OCA], [http://pdbe.org/6wgx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6wgx RCSB], [http://www.ebi.ac.uk/pdbsum/6wgx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6wgx ProSAT]</span></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=U0D:4-(1-{1-[2-(dimethylamino)ethyl]piperidin-4-yl}-4-[4-(trifluoromethyl)phenyl]-1H-imidazol-5-yl)-N-(3,5-dimethylphenyl)pyrimidin-2-amine'>U0D</scene></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://proteopedia.org/fgij/fg.htm?mol=6wgx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6wgx OCA], [http://pdbe.org/6wgx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6wgx RCSB], [http://www.ebi.ac.uk/pdbsum/6wgx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6wgx ProSAT]</span></td></tr> | ||
</table> | </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> | ||
| + | == 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 == | ||
| + | Bromodomain and extra-terminal (BET) family proteins, BRD2-4 and T, are important drug targets; however, the biological functions of each bromodomain remain ill-defined. Chemical probes that selectively inhibit a single BET bromodomain are lacking, although pan inhibitors of the first (D1), and second (D2), bromodomain are known. Here, we develop selective BET D1 inhibitors with preferred binding to of BRD4 D1. In competitive inhibition assays we show that our lead compound is 9-33 fold selective for BRD4 D1 over the other BET bromodomains. X-ray crystallography supports a role for the selectivity based on reorganization of a non-conserved lysine and displacement of an additional structured water in the BRD4 D1 binding site relative to our prior lead. Whereas pan-D1 inhibitors displace BRD4 from MYC enhancers, BRD4 D1 inhibition in MM.1S cells is insufficient for stopping Myc expression and may lead to its upregulation. Future analysis of BRD4 D1 gene regulation may shed light on differential BET bromodomain functions. | ||
| + | |||
| + | Selective N-terminal BRD4 bromodomain inhibitors by targeting non-conserved residues and structured water displacement.,Pomerantz WCK, Cui H, Divakaran A, Pandey AK, Johnson JA, Zahid H, Hoell ZJ, Ellingson MO, Shi K, Aihara H, Harki DA Angew Chem Int Ed Engl. 2020 Sep 24. doi: 10.1002/anie.202008625. PMID:32975004<ref>PMID:32975004</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6wgx" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Human]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Aihara H]] | + | [[Category: Aihara, H]] |
| - | [[Category: Cui H]] | + | [[Category: Cui, H]] |
| - | [[Category: Johnson | + | [[Category: Johnson, J A]] |
| - | [[Category: Pomerantz | + | [[Category: Pomerantz, W C.K]] |
| - | [[Category: Shi K]] | + | [[Category: Shi, K]] |
| + | [[Category: Brd4]] | ||
| + | [[Category: Gene regulation]] | ||
| + | [[Category: Gene regulation-inhibitor complex]] | ||
Revision as of 08:12, 2 December 2020
Cocrystal of BRD4(D1) with a selective inhibitor
| |||||||||||
