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6j3o

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

Structural highlights

6j3o is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.11Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.^[1] ^[2] ^[3] ^[4]

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^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Yang XJ, Ogryzko VV, Nishikawa J, Howard BH, Nakatani Y. A p300/CBP-associated factor that competes with the adenoviral oncoprotein E1A. Nature. 1996 Jul 25;382(6589):319-24. PMID:8684459 doi:10.1038/382319a0
↑ Zhang W, Bieker JJ. Acetylation and modulation of erythroid Kruppel-like factor (EKLF) activity by interaction with histone acetyltransferases. Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):9855-60. PMID:9707565
↑ Martinez-Balbas MA, Bauer UM, Nielsen SJ, Brehm A, Kouzarides T. Regulation of E2F1 activity by acetylation. EMBO J. 2000 Feb 15;19(4):662-71. PMID:10675335 doi:10.1093/emboj/19.4.662
↑ Lin R, Tao R, Gao X, Li T, Zhou X, Guan KL, Xiong Y, Lei QY. Acetylation stabilizes ATP-citrate lyase to promote lipid biosynthesis and tumor growth. Mol Cell. 2013 Aug 22;51(4):506-18. doi: 10.1016/j.molcel.2013.07.002. Epub 2013 , Aug 8. PMID:23932781 doi:http://dx.doi.org/10.1016/j.molcel.2013.07.002
↑ Huang L, Li H, Li L, Niu L, Seupel R, Wu C, Cheng W, Chen C, Ding B, Brennan PE, Yang S. 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. J Med Chem. 2019 Apr 30. doi: 10.1021/acs.jmedchem.9b00096. PMID:30998845 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b00096

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6j3o"

@@ Line 3: / Line 3: @@
 <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>
+<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>
-</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>
+</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>
-<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>
+<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>
+<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>
 </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>
+[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>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 22: / Line 23: @@
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Brennan, P E]]
+[[Category: Brennan PE]]
-[[Category: Huang, L Y]]
+[[Category: Huang LY]]
-[[Category: Li, G B]]
+[[Category: Li GB]]
-[[Category: Li, H]]
+[[Category: Li H]]
-[[Category: Li, L L]]
+[[Category: Li LL]]
-[[Category: Niu, L]]
+[[Category: Niu L]]
-[[Category: Seupel, R]]
+[[Category: Seupel R]]
-[[Category: Wu, C Y]]
+[[Category: Wu CY]]
-[[Category: Yang, S Y]]
+[[Category: Yang SY]]
-[[Category: Yu, Y M]]
+[[Category: Yu YM]]
-[[Category: Crystal structure of the human pcaf bromodomain in complex with compound 12]]
-[[Category: Transferase]]

6j3o

From Proteopedia

Current revision

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

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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