6j3o
From Proteopedia
(Difference between revisions)
| Line 1: | Line 1: | ||
| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of the human PCAF bromodomain in complex with compound 12== | |
| + | <StructureSection load='6j3o' size='340' side='right'caption='[[6j3o]], [[Resolution|resolution]] 2.11Å' 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. | ||
| - | + | 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> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: | + | <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 | + | [[Category: Li, L L]] |
| - | + | ||
| - | + | ||
[[Category: Niu, L]] | [[Category: Niu, L]] | ||
| - | [[Category: | + | [[Category: Seupel, R]] |
| - | [[Category: | + | [[Category: Wu, C Y]] |
| - | [[Category: | + | [[Category: Yang, S Y]] |
| - | [[Category: | + | [[Category: Yu, Y M]] |
| + | [[Category: Crystal structure of the human pcaf bromodomain in complex with compound 12]] | ||
| + | [[Category: Transferase]] | ||
Revision as of 08:50, 1 May 2019
Crystal structure of the human PCAF bromodomain in complex with compound 12
| |||||||||||
