6j3p

From Proteopedia

(Difference between revisions)

Revision as of 07:35, 23 May 2019

Crystal structure of the human GCN5 bromodomain in complex with compound (R,R)-36n

Structural highlights

6j3p is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	KAT2A, GCN5, GCN5L2 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[KAT2A_HUMAN] Functions as a histone acetyltransferase (HAT) to promote transcriptional activation. Acetylation of histones gives a specific tag for epigenetic transcription activation. Has significant histone acetyltransferase activity with core histones, but not with nucleosome core particles. Also acetylates non-histone proteins, such as CEBPB (PubMed:17301242). Component of the ATAC complex, a complex with histone acetyltransferase activity on histones H3 and H4. 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]

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^[3]

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

References

↑ Wiper-Bergeron N, Salem HA, Tomlinson JJ, Wu D, Hache RJ. Glucocorticoid-stimulated preadipocyte differentiation is mediated through acetylation of C/EBPbeta by GCN5. Proc Natl Acad Sci U S A. 2007 Feb 20;104(8):2703-8. Epub 2007 Feb 14. PMID:17301242 doi:http://dx.doi.org/10.1073/pnas.0607378104
↑ Guelman S, Kozuka K, Mao Y, Pham V, Solloway MJ, Wang J, Wu J, Lill JR, Zha J. The double-histone-acetyltransferase complex ATAC is essential for mammalian development. Mol Cell Biol. 2009 Mar;29(5):1176-88. doi: 10.1128/MCB.01599-08. Epub 2008 Dec, 22. PMID:19103755 doi:10.1128/MCB.01599-08
↑ 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/6j3p"

@@ Line 3: / Line 3: @@
 <StructureSection load='6j3p' size='340' side='right'caption='[[6j3p]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6j3p]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6J3P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6J3P FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6j3p]] is a 2 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=6J3P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6J3P FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=B8O:2-{[(3R,5R)-5-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-methylpiperidin-3-yl]amino}-3-methyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one'>B8O</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">KAT2A, GCN5, GCN5L2 ([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=6j3p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6j3p OCA], [http://pdbe.org/6j3p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6j3p RCSB], [http://www.ebi.ac.uk/pdbsum/6j3p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6j3p ProSAT]</span></td></tr>
 </table>
@@ Line 22: / Line 23: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Large Structures]]
 [[Category: Huang, L Y]]

6j3p

From Proteopedia

Revision as of 07:35, 23 May 2019

Crystal structure of the human GCN5 bromodomain in complex with compound (R,R)-36n

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox