7wx2: Difference between revisions
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==CBP-BrD complexed with NEO2734== | ==CBP-BrD complexed with NEO2734== | ||
<StructureSection load='7wx2' size='340' side='right'caption='[[7wx2]]' scene=''> | <StructureSection load='7wx2' size='340' side='right'caption='[[7wx2]], [[Resolution|resolution]] 1.24Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7WX2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7WX2 FirstGlance]. <br> | <table><tr><td colspan='2'>[[7wx2]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7WX2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7WX2 FirstGlance]. <br> | ||
</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=7wx2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7wx2 OCA], [https://pdbe.org/7wx2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7wx2 RCSB], [https://www.ebi.ac.uk/pdbsum/7wx2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7wx2 ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7OW:1,3-dimethyl-5-[2-(oxan-4-yl)-3-[2-(trifluoromethyloxy)ethyl]benzimidazol-5-yl]pyridin-2-one'>7OW</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=7wx2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7wx2 OCA], [https://pdbe.org/7wx2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7wx2 RCSB], [https://www.ebi.ac.uk/pdbsum/7wx2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7wx2 ProSAT]</span></td></tr> | |||
</table> | </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> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
CUB domain-containing protein 1 (CDCP1), a transmembrane protein with tumor pro-metastatic activity, is highly expressed in late-stage and castrate-resistant prostate cancer (CRPC). However, the molecular mechanism driving CDCP1 overexpression in CRPC progress remains elusive. Here we report that transcription cofactors BRD4 and CBP/p300 co-regulate transcriptional expression of CDCP1 in CRPC tumorigenesis. In contrast to androgen receptor (AR) in CRPC, increased expression of BRD4 and CBP/p300 is strongly correlated with CDCP1 gene amplification. Combined knockdown or dual-inhibition of BRD4 and CBP/p300 down-regulated CDCP1 transcription and downstream PI3K/AKT and/or SRC/MAPK signaling pathways in CRPC cells much more so than single-protein perturbation. Our biochemical and structural analyses further showed that NEO2734, a dual-inhibitor targeting BRD4 and p300 bromodomains exhibits greater efficacy than single inhibitors for BRD4 or CBP/p300 in suppressing CDCP1 transcriptional expression and its downstream signaling pathways in CRPC cell proliferation and metastasis. Our study illustrates that targeting CDCP1 through dual-inhibition of BRD4 and CBP/p300 represents a synergistic therapeutic strategy for new treatment of CRPC. | |||
Targeting CDCP1 gene transcription coactivated by BRD4 and CBP/p300 in castration-resistant prostate cancer.,Ji D, Shang G, Wei E, Jia Y, Wang C, Zhang Q, Zeng L Oncogene. 2022 Jun;41(23):3251-3262. doi: 10.1038/s41388-022-02327-5. Epub 2022, May 5. PMID:35513563<ref>PMID:35513563</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7wx2" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Lei | [[Category: Lei, J D]] | ||
[[Category: Zeng L]] | [[Category: Zeng, L]] | ||
[[Category: Bromodomain]] | |||
[[Category: Cbp]] | |||
[[Category: Complex]] | |||
[[Category: Neo2734]] | |||
[[Category: Protein binding]] | |||