7lje

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==Discovery of Spirohydantoins as Selective, Orally Bioavailable Inhibitors of p300/CBP Histone Acetyltransferases==
==Discovery of Spirohydantoins as Selective, Orally Bioavailable Inhibitors of p300/CBP Histone Acetyltransferases==
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<StructureSection load='7lje' size='340' side='right'caption='[[7lje]]' scene=''>
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<StructureSection load='7lje' size='340' side='right'caption='[[7lje]], [[Resolution|resolution]] 2.61&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LJE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LJE FirstGlance]. <br>
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<table><tr><td colspan='2'>[[7lje]] is a 4 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=7LJE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LJE FirstGlance]. <br>
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</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=7lje FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lje OCA], [https://pdbe.org/7lje PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lje RCSB], [https://www.ebi.ac.uk/pdbsum/7lje PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lje ProSAT]</span></td></tr>
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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]] 2.607&#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=Y2P:2-[4-[(3R,4S)-3-fluoro-1-[2-[(4-fluorophenyl)methyl-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]amino]-2-oxo-ethyl]-2,5-dioxo-spiro[imidazolidine-4,1-indane]-5-yl]pyrazol-1-yl]-N-methyl-acetamide'>Y2P</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=7lje FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lje OCA], [https://pdbe.org/7lje PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lje RCSB], [https://www.ebi.ac.uk/pdbsum/7lje PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lje ProSAT]</span></td></tr>
</table>
</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/EP300_HUMAN EP300_HUMAN] Note=Defects in EP300 may play a role in epithelial cancer. Note=Chromosomal aberrations involving EP300 may be a cause of acute myeloid leukemias. Translocation t(8;22)(p11;q13) with KAT6A. Defects in EP300 are the cause of Rubinstein-Taybi syndrome type 2 (RSTS2) [MIM:[https://omim.org/entry/613684 613684]. A disorder characterized by craniofacial abnormalities, postnatal growth deficiency, broad thumbs, broad big toes, mental retardation and a propensity for development of malignancies. Some individuals with RSTS2 have less severe mental impairment, more severe microcephaly, and a greater degree of changes in facial bone structure than RSTS1 patients.<ref>PMID:15706485</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/EP300_HUMAN EP300_HUMAN] Functions as histone acetyltransferase and regulates transcription via chromatin remodeling. Acetylates all four core histones in nucleosomes. Histone acetylation gives an epigenetic tag for transcriptional activation. Mediates cAMP-gene regulation by binding specifically to phosphorylated CREB protein. Also functions as acetyltransferase for nonhistone targets. Acetylates 'Lys-131' of ALX1 and acts as its coactivator in the presence of CREBBP. Acetylates SIRT2 and is proposed to indirectly increase the transcriptional activity of TP53 through acetylation and subsequent attenuation of SIRT2 deacetylase function. Acetylates HDAC1 leading to its inactivation and modulation of transcription. Acts as a TFAP2A-mediated transcriptional coactivator in presence of CITED2. Plays a role as a coactivator of NEUROD1-dependent transcription of the secretin and p21 genes and controls terminal differentiation of cells in the intestinal epithelium. Promotes cardiac myocyte enlargement. Can also mediate transcriptional repression. Binds to and may be involved in the transforming capacity of the adenovirus E1A protein. 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. Acetylates FOXO1 and enhances its transcriptional activity.<ref>PMID:11701890</ref> <ref>PMID:10733570</ref> <ref>PMID:11430825</ref> <ref>PMID:12586840</ref> <ref>PMID:12929931</ref> <ref>PMID:15186775</ref> <ref>PMID:15890677</ref> <ref>PMID:16762839</ref> <ref>PMID:18722353</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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p300 and CREB-binding protein (CBP) are essential for a multitude of cellular processes. Dysregulation of p300/CBP histone acetyltransferase activity is linked to a broad spectrum of human diseases including cancers. A novel drug-like spirohydantoin (21) has been discovered as a selective orally bioavailable inhibitor of p300/CBP histone acetyltransferase. Lead compound 21 is more potent than the first-in-class lead A-485 in both enzymatic and cellular assays and lacks the off-target inhibition of dopamine and serotonin transporters, that was observed with A-485.
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Discovery of Spirohydantoins as Selective, Orally Bioavailable Inhibitors of p300/CBP Histone Acetyltransferases.,Ji Z, Clark RF, Bhat V, Matthew Hansen T, Lasko LM, Bromberg KD, Manaves V, Algire M, Martin R, Qiu W, Torrent M, Jakob CG, Liu H, Cole PA, Marmorstein R, Kesicki EA, Lai A, Michaelides MR Bioorg Med Chem Lett. 2021 Feb 22:127854. doi: 10.1016/j.bmcl.2021.127854. PMID:33631370<ref>PMID:33631370</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 7lje" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Histone acetyltransferase 3D structures|Histone acetyltransferase 3D structures]]
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Jakob CG]]
[[Category: Jakob CG]]

Current revision

Discovery of Spirohydantoins as Selective, Orally Bioavailable Inhibitors of p300/CBP Histone Acetyltransferases

PDB ID 7lje

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