5o3e: Difference between revisions

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 <StructureSection load='5o3e' size='340' side='right' caption='[[5o3e]], [[Resolution|resolution]] 1.40&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5o3e]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5O3E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5O3E FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5o3e]] is a 1 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=5O3E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5O3E FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9HW:(2~{R})-2-[(4~{S})-6-(4-chlorophenyl)-8-methoxy-1-methyl-4~{H}-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-~{N}-ethyl-propanamide'>9HW</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DQW:(2~{S})-1-[(2~{S})-2-oxidanylpropoxy]propan-2-ol'>DQW</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BRD2, KIAA9001, RING3 ([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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5o3e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5o3e OCA], [http://pdbe.org/5o3e PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5o3e RCSB], [http://www.ebi.ac.uk/pdbsum/5o3e PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5o3e ProSAT]</span></td></tr>
 </table>
 == Function ==
 [[http://www.uniprot.org/uniprot/BRD2_HUMAN BRD2_HUMAN]] May play a role in spermatogenesis or folliculogenesis (By similarity). Binds hyperacetylated chromatin and plays a role in the regulation of transcription, probably by chromatin remodeling. Regulates transcription of the CCND1 gene. Plays a role in nucleosome assembly.<ref>PMID:18406326</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Allele-specific chemical genetics enables selective inhibition within families of highly-conserved proteins. The four BET (bromodomain &amp; extra-terminal domain) proteins - BRD2, BRD3, BRD4 and BRDT bind acetylated chromatin via their bromodomains and regulate processes such as cell proliferation and inflammation. BET bromodomains are of particular interest, as they are attractive therapeutic targets but existing inhibitors are pan-selective. We previously established a bump-&amp;-hole system for the BET bromodomains, pairing a leucine/alanine mutation with an ethyl-derived analogue of an established benzodiazepine scaffold. Here we optimize upon this system with the introduction of a more conservative and less disruptive leucine/valine mutation. Extensive structure-activity-relationships of diverse benzodiazepine analogues guided the development of potent, mutant-selective inhibitors with desirable physiochemical properties. The active enantiomer of our best compound - 9-ME-1 - shows approximately 200 nM potency, &gt;100-fold selectivity for the L/V mutant over wild-type and excellent DMPK properties. Through a variety of in vitro and cellular assays we validate the capabilities of our optimized system, and then utilize it to compare the relative importance of the first and second bromodomains to chromatin binding. These experiments confirm the primacy of the first bromodomain in all BET proteins, but also significant variation in the importance of the second bromodomain. We also show that, despite having a minor role in chromatin recognition, BRD4 BD2 is still essential for gene expression, likely through the recruitment of non-histone proteins. The disclosed inhibitor:mutant pair provides a powerful tool for future cellular and in vivo target validation studies.
+Optimization of a "bump-and-hole" approach to allele-selective BET bromodomain inhibition.,Runcie AC, Zengerle M, Chan KH, Testa A, van Beurden L, Baud MGJ, Epemolu O, Ellis LCJ, Read KD, Coulthard V, Brien A, Ciulli A Chem Sci. 2018 Jan 24;9(9):2452-2468. doi: 10.1039/c7sc02536j. eCollection 2018, Mar 7. PMID:29732121<ref>PMID:29732121</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 5o3e" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Bromodomain-containing protein|Bromodomain-containing protein]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Chan, K H]]
 [[Category: Ciulli, A]]
 [[Category: Runcie, A C]]
 [[Category: Transcription]]