2d82

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{{STRUCTURE_2d82| PDB=2d82 | SCENE= }}
 
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===Target Structure-Based Discovery of Small Molecules that Block Human p53 and CREB Binding Protein (CBP) Association===
 
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{{ABSTRACT_PUBMED_16426974}}
 
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==Disease==
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==Target Structure-Based Discovery of Small Molecules that Block Human p53 and CREB Binding Protein (CBP) Association==
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[[http://www.uniprot.org/uniprot/CBP_HUMAN CBP_HUMAN]] Note=Chromosomal aberrations involving CREBBP may be a cause of acute myeloid leukemias. Translocation t(8;16)(p11;p13) with KAT6A; translocation t(11;16)(q23;p13.3) with MLL/HRX; translocation t(10;16)(q22;p13) with KAT6B. KAT6A-CREBBP may induce leukemia by inhibiting RUNX1-mediated transcription. Defects in CREBBP are a cause of Rubinstein-Taybi syndrome type 1 (RSTS1) [MIM:[http://omim.org/entry/180849 180849]]. RSTS1 is an autosomal dominant disorder characterized by craniofacial abnormalities, broad thumbs, broad big toes, mental retardation and a propensity for development of malignancies.<ref>PMID:11331617</ref><ref>PMID:12114483</ref><ref>PMID:12566391</ref><ref>PMID:15706485</ref>
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<StructureSection load='2d82' size='340' side='right'caption='[[2d82]]' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2d82]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2D82 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2D82 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">Solution NMR</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=TTR:9-ACETYL-2,3,4,9-TETRAHYDRO-1H-CARBAZOL-1-ONE'>TTR</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=2d82 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2d82 OCA], [https://pdbe.org/2d82 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2d82 RCSB], [https://www.ebi.ac.uk/pdbsum/2d82 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2d82 ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/CBP_HUMAN CBP_HUMAN] Note=Chromosomal aberrations involving CREBBP may be a cause of acute myeloid leukemias. Translocation t(8;16)(p11;p13) with KAT6A; translocation t(11;16)(q23;p13.3) with MLL/HRX; translocation t(10;16)(q22;p13) with KAT6B. KAT6A-CREBBP may induce leukemia by inhibiting RUNX1-mediated transcription. Defects in CREBBP are a cause of Rubinstein-Taybi syndrome type 1 (RSTS1) [MIM:[https://omim.org/entry/180849 180849]. RSTS1 is an autosomal dominant disorder characterized by craniofacial abnormalities, broad thumbs, broad big toes, mental retardation and a propensity for development of malignancies.<ref>PMID:11331617</ref> <ref>PMID:12114483</ref> <ref>PMID:12566391</ref> <ref>PMID:15706485</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/CBP_HUMAN CBP_HUMAN] Acetylates histones, giving a specific tag for transcriptional activation. Also acetylates non-histone proteins, like NCOA3 and FOXO1. Binds specifically to phosphorylated CREB and enhances its transcriptional activity toward cAMP-responsive genes. Acts as a coactivator of ALX1 in the presence of EP300.<ref>PMID:9707565</ref> <ref>PMID:11154691</ref> <ref>PMID:12738767</ref> <ref>PMID:12929931</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/d8/2d82_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2d82 ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Lysine acetylation of human tumor suppressor p53 in response to cellular stress signals is required for its function as a transcription factor that regulates cell cycle arrest, senescence, or apoptosis. Here, we report small molecules that block lysine 382-acetylated p53 association with the bromodomain of the coactivator CBP, an interaction essential for p53-induced transcription of the cell cycle inhibitor p21 in response to DNA damage. These chemicals were discovered in target structure-guided nuclear magnetic resonance spectroscopy screening of a focused chemical library constructed based on the structural knowledge of CBP bromodomain/p53-AcK382 binding. Structural characterization shows that these chemicals inhibit CBP/p53 association by binding to the acetyl-lysine binding site of the bromodomain. Cell-based functional assays demonstrate that the lead chemicals can modulate p53 stability and function in response to DNA damage.
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==Function==
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Target structure-based discovery of small molecules that block human p53 and CREB binding protein association.,Sachchidanand, Resnick-Silverman L, Yan S, Mutjaba S, Liu WJ, Zeng L, Manfredi JJ, Zhou MM Chem Biol. 2006 Jan;13(1):81-90. PMID:16426974<ref>PMID:16426974</ref>
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[[http://www.uniprot.org/uniprot/CBP_HUMAN CBP_HUMAN]] Acetylates histones, giving a specific tag for transcriptional activation. Also acetylates non-histone proteins, like NCOA3 and FOXO1. Binds specifically to phosphorylated CREB and enhances its transcriptional activity toward cAMP-responsive genes. Acts as a coactivator of ALX1 in the presence of EP300.<ref>PMID:9707565</ref><ref>PMID:11154691</ref><ref>PMID:12738767</ref><ref>PMID:12929931</ref>
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[2d82]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2D82 OCA].
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</div>
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<div class="pdbe-citations 2d82" style="background-color:#fffaf0;"></div>
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==Reference==
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==See Also==
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<ref group="xtra">PMID:016426974</ref><references group="xtra"/><references/>
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*[[CREB-binding protein 3D structures|CREB-binding protein 3D structures]]
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[[Category: Histone acetyltransferase]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Liu, W J.]]
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[[Category: Large Structures]]
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[[Category: Manfredi, J J.]]
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[[Category: Liu WJ]]
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[[Category: Mujtaba, S.]]
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[[Category: Manfredi JJ]]
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[[Category: Resnick-Silverman, L.]]
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[[Category: Mujtaba S]]
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[[Category: Resnick-Silverman L]]
[[Category: Sachchidanand]]
[[Category: Sachchidanand]]
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[[Category: Yan, S.]]
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[[Category: Yan S]]
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[[Category: Zeng, L.]]
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[[Category: Zeng L]]
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[[Category: Zhou, M M.]]
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[[Category: Zhou MM]]
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[[Category: 9-acetyl-2]]
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[[Category: 9-tetrahydro-carbazol-1-one]]
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[[Category: Bromodomain]]
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[[Category: Cbp]]
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[[Category: Chemical ligand]]
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[[Category: Creb]]
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[[Category: P53]]
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[[Category: Transferase]]
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Current revision

Target Structure-Based Discovery of Small Molecules that Block Human p53 and CREB Binding Protein (CBP) Association

PDB ID 2d82

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