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New page: left|200px<br /> <applet load="2d82" size="450" color="white" frame="true" align="right" spinBox="true" caption="2d82" /> '''Target Structure-Based Discovery of Small M...
 
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[[Image:2d82.gif|left|200px]]<br />
<applet load="2d82" size="450" color="white" frame="true" align="right" spinBox="true"
caption="2d82" />
'''Target Structure-Based Discovery of Small Molecules that Block Human p53 and CREB Binding Protein (CBP) Association'''<br />


==Overview==
==Target Structure-Based Discovery of Small Molecules that Block Human p53 and CREB Binding Protein (CBP) Association==
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.
<StructureSection load='2d82' size='340' side='right'caption='[[2d82]]' scene=''>
== Structural highlights ==
<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>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr>
<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>
<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>
</table>
== Disease ==
[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>
== Function ==
[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>
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/d8/2d82_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</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].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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.


==Disease==
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>
Known diseases associated with this structure: Blue-cone monochromacy OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=303900 303900]], Colorblindness, protan OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=303900 303900]], Rubenstein-Taybi syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600140 600140]]


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
2D82 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with TTR as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Histone_acetyltransferase Histone acetyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.48 2.3.1.48] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2D82 OCA].
</div>
<div class="pdbe-citations 2d82" style="background-color:#fffaf0;"></div>


==Reference==
==See Also==
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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16426974 16426974]
*[[CREB-binding protein 3D structures|CREB-binding protein 3D structures]]
[[Category: Histone acetyltransferase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Liu, W.J.]]
[[Category: Liu WJ]]
[[Category: Manfredi, J.J.]]
[[Category: Manfredi JJ]]
[[Category: Mujtaba, S.]]
[[Category: Mujtaba S]]
[[Category: Resnick-Silverman, L.]]
[[Category: Resnick-Silverman L]]
[[Category: Sachchidanand]]
[[Category: Sachchidanand]]
[[Category: Yan, S.]]
[[Category: Yan S]]
[[Category: Zeng, L.]]
[[Category: Zeng L]]
[[Category: Zhou, M.M.]]
[[Category: Zhou MM]]
[[Category: TTR]]
[[Category: 3]]
[[Category: 4]]
[[Category: 9-acetyl-2]]
[[Category: 9-tetrahydro-carbazol-1-one]]
[[Category: bromodomain]]
[[Category: cbp]]
[[Category: chemical ligand]]
[[Category: creb]]
[[Category: nmr structure]]
[[Category: p53]]
 
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