View source for 5nu3


==Crystal structure of the human bromodomain of CREBBP bound to the inhibitor XDM-CBP==
<StructureSection load='5nu3' size='340' side='right' caption='[[5nu3]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5nu3]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NU3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5NU3 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=99E:~{N}-[[2,8-bis(oxidanyl)naphthalen-1-yl]methyl]-4-ethanoyl-3-ethyl-5-methyl-1~{H}-pyrrole-2-carboxamide'>99E</scene>, <scene name='pdbligand=BU3:(R,R)-2,3-BUTANEDIOL'>BU3</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </span></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=5nu3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nu3 OCA], [http://pdbe.org/5nu3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5nu3 RCSB], [http://www.ebi.ac.uk/pdbsum/5nu3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5nu3 ProSAT]</span></td></tr>
</table>
== Disease ==
[[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>  
== Function ==
[[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>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
BET bromodomain inhibitors are widely used both as chemical tools to study the biological role of their targets in living organisms, and as candidates for drug development against several cancer variants and human disorders. However, non-BET bromodomains such as those in p300 and CBP are less studied. Here, we introduce XDM-CBP, a highly potent and selective inhibitor for the bromodomains of CBP and p300 derived from a pan-selective BET BRD-binding fragment. In addition to X-ray crystal structure analysis and thermodynamic profiling, we used XDM-CBP in in vitro cell screenings of several cancer cell lines to study its inhibitory potential on cancer cell proliferation. Our results demonstrate that XDM-CBP is a potent and selective CBP/p300 inhibitor that acts on specific cancer cell lines, in particular malignant melanoma, breast cancer, and leukemia.

Beyond the BET family: targeting CBP/p300 with 4-acyl pyrroles.,Hugle M, Lucas X, Ostrovskyi D, Regenass P, Gerhardt S, Einsle O, Hau M, Jung M, Breit B, Gunther S, Wohlwend D Angew Chem Int Ed Engl. 2017 Aug 2. doi: 10.1002/anie.201705516. PMID:28766825<ref>PMID:28766825</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5nu3" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Histone acetyltransferase]]
[[Category: Huegle, M]]
[[Category: Wohlwend, D]]
[[Category: Bromodomain]]
[[Category: Crebbp]]
[[Category: Epigenetic]]
[[Category: Protein-inhibitor complex]]
[[Category: Transferase]]