6j3o

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'''Unreleased structure'''
 
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The entry 6j3o is ON HOLD
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==Crystal structure of the human PCAF bromodomain in complex with compound 12==
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<StructureSection load='6j3o' size='340' side='right'caption='[[6j3o]], [[Resolution|resolution]] 2.11&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[6j3o]] is a 2 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=6J3O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6J3O FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.11&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=B4L:3-methyl-2-[[(3~{R})-1-methylpiperidin-3-yl]amino]-5~{H}-pyrrolo[3,2-d]pyrimidin-4-one'>B4L</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6j3o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6j3o OCA], [https://pdbe.org/6j3o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6j3o RCSB], [https://www.ebi.ac.uk/pdbsum/6j3o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6j3o ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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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.
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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>
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Description: Crystal structure of the human PCAF bromodomain in complex with compound 12
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Seupel, R]]
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<div class="pdbe-citations 6j3o" style="background-color:#fffaf0;"></div>
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[[Category: Li, H]]
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== References ==
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[[Category: Li, L.L]]
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<references/>
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[[Category: Yu, Y.M]]
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__TOC__
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[[Category: Brennan, P.E]]
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</StructureSection>
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[[Category: Niu, L]]
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[[Category: Homo sapiens]]
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[[Category: Li, G.B]]
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[[Category: Large Structures]]
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[[Category: Yang, S.Y]]
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[[Category: Brennan PE]]
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[[Category: Huang, L.Y]]
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[[Category: Huang LY]]
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[[Category: Wu, C.Y]]
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[[Category: Li GB]]
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[[Category: Li H]]
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[[Category: Li LL]]
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[[Category: Niu L]]
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[[Category: Seupel R]]
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[[Category: Wu CY]]
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[[Category: Yang SY]]
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[[Category: Yu YM]]

Current revision

Crystal structure of the human PCAF bromodomain in complex with compound 12

PDB ID 6j3o

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