6j3o: Difference between revisions

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'''Unreleased structure'''


The entry 6j3o is ON HOLD until Paper Publication
==Crystal structure of the human PCAF bromodomain in complex with compound 12==
<StructureSection load='6j3o' size='340' side='right'caption='[[6j3o]], [[Resolution|resolution]] 2.11&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6j3o]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6J3O OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6J3O FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=B4L:3-methyl-2-{[(3R)-1-methylpiperidin-3-yl]amino}-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one'>B4L</scene></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=6j3o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6j3o OCA], [http://pdbe.org/6j3o PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6j3o RCSB], [http://www.ebi.ac.uk/pdbsum/6j3o PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6j3o ProSAT]</span></td></tr>
</table>
== Function ==
[[http://www.uniprot.org/uniprot/KAT2B_HUMAN KAT2B_HUMAN]] Functions as a histone acetyltransferase (HAT) to promote transcriptional activation. Has significant histone acetyltransferase activity with core histones (H3 and H4), and also with nucleosome core particles. Also acetylates non-histone proteins, such as ACLY. Inhibits cell-cycle progression and counteracts the mitogenic activity of the adenoviral oncoprotein E1A. In case of HIV-1 infection, it is recruited by the viral protein Tat. Regulates Tat's transactivating activity and may help inducing chromatin remodeling of proviral genes.<ref>PMID:8684459</ref> <ref>PMID:9707565</ref> <ref>PMID:10675335</ref> <ref>PMID:23932781</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Herein, we report the discovery of a series of new P300/CBP-associated factor (PCAF) bromodomain (BRD) inhibitors, which were obtained through a hit discovery process and subsequent structure-based optimization and structure-activity relationship analyses toward a retrieved hit compound (12). Among these inhibitors, ( R, R)-36n is the most potent one with an IC50 of 7 nM in homogeneous time-resolved fluorescence assay and a KD of 78 nM in isothermal titration calorimetry assay. This compound also exhibited activity against GCN5 and FALZ, but weak or no activity against other 29 BRD proteins and 422 kinases, indicating considerable selectivity. X-ray cocrystal structure analysis revealed the molecular interaction mode and the precise stereochemistry required for bioactivity. Cellular activity, preliminary RNA-seq analysis, and pharmacokinetic properties were also examined for this compound. Collectively, this study provides a versatile tool molecule to explore molecular mechanisms of PCAF BRD regulation and also offers a new lead compound for drug discovery targeting PCAF.


Authors: Huang, L.Y., Li, H., Li, L.L., Niu, L., Seupel, R., Wu, C.Y., Li, G.B., Yu, Y.M., Brennan, P.E., Yang, S.Y.
Discovery of Pyrrolo[3,2- d]pyrimidin-4-one Derivatives as a New Class of Potent and Cell-Active Inhibitors of P300/CBP-Associated Factor Bromodomain.,Huang L, Li H, Li L, Niu L, Seupel R, Wu C, Cheng W, Chen C, Ding B, Brennan PE, Yang S J Med Chem. 2019 Apr 30. doi: 10.1021/acs.jmedchem.9b00096. PMID:30998845<ref>PMID:30998845</ref>


Description: Crystal structure of the human PCAF bromodomain in complex with compound 12
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
[[Category: Seupel, R]]
<div class="pdbe-citations 6j3o" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Brennan, P E]]
[[Category: Huang, L Y]]
[[Category: Li, G B]]
[[Category: Li, H]]
[[Category: Li, H]]
[[Category: Li, L.L]]
[[Category: Li, L L]]
[[Category: Yu, Y.M]]
[[Category: Brennan, P.E]]
[[Category: Niu, L]]
[[Category: Niu, L]]
[[Category: Li, G.B]]
[[Category: Seupel, R]]
[[Category: Yang, S.Y]]
[[Category: Wu, C Y]]
[[Category: Huang, L.Y]]
[[Category: Yang, S Y]]
[[Category: Wu, C.Y]]
[[Category: Yu, Y M]]
[[Category: Crystal structure of the human pcaf bromodomain in complex with compound 12]]
[[Category: Transferase]]
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