View source for 8ru3


==Crystal structure of beta-catenin in complex with alpha-helical peptide inhibitor==
<StructureSection load='8ru3' size='340' side='right'caption='[[8ru3]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8ru3]] is a 2 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=8RU3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8RU3 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.001&#8491;</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=8ru3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ru3 OCA], [https://pdbe.org/8ru3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ru3 RCSB], [https://www.ebi.ac.uk/pdbsum/8ru3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ru3 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/CTNB1_HUMAN CTNB1_HUMAN] Defects in CTNNB1 are associated with colorectal cancer (CRC) [MIM:[https://omim.org/entry/114500 114500].  Note=Activating mutations in CTNNB1 have oncogenic activity resulting in tumor development. Somatic mutations are found in various tumor types, including colon cancers, ovarian and prostate carcinomas, hepatoblastoma (HB), hepatocellular carcinoma (HCC). HBs are malignant embryonal tumors mainly affecting young children in the first three years of life.  Defects in CTNNB1 are a cause of pilomatrixoma (PTR) [MIM:[https://omim.org/entry/132600 132600]; a common benign skin tumor.<ref>PMID:11703283</ref> <ref>PMID:12027456</ref> <ref>PMID:10192393</ref>   Defects in CTNNB1 are a cause of medulloblastoma (MDB) [MIM:[https://omim.org/entry/155255 155255]. MDB is a malignant, invasive embryonal tumor of the cerebellum with a preferential manifestation in children.<ref>PMID:12027456</ref> <ref>PMID:10666372</ref>   Defects in CTNNB1 are a cause of susceptibility to ovarian cancer (OC) [MIM:[https://omim.org/entry/167000 167000]. Ovarian cancer common malignancy originating from ovarian tissue. Although many histologic types of ovarian neoplasms have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease.  Note=A chromosomal aberration involving CTNNB1 is found in salivary gland pleiomorphic adenomas, the most common benign epithelial tumors of the salivary gland. Translocation t(3;8)(p21;q12) with PLAG1.  Defects in CTNNB1 may be a cause of mesothelioma malignant (MESOM) [MIM:[https://omim.org/entry/156240 156240]. An aggressive neoplasm of the serosal lining of the chest. It appears as broad sheets of cells, with some regions containing spindle-shaped, sarcoma-like cells and other regions showing adenomatous patterns. Pleural mesotheliomas have been linked to exposure to asbestos.<ref>PMID:11464291</ref> 
== Function ==
[https://www.uniprot.org/uniprot/CTNB1_HUMAN CTNB1_HUMAN] Key downstream component of the canonical Wnt signaling pathway. In the absence of Wnt, forms a complex with AXIN1, AXIN2, APC, CSNK1A1 and GSK3B that promotes phosphorylation on N-terminal Ser and Thr residues and ubiquitination of CTNNB1 via BTRC and its subsequent degradation by the proteasome. In the presence of Wnt ligand, CTNNB1 is not ubiquitinated and accumulates in the nucleus, where it acts as a coactivator for transcription factors of the TCF/LEF family, leading to activate Wnt responsive genes. Involved in the regulation of cell adhesion. Acts as a negative regulator of centrosome cohesion. Involved in the CDK2/PTPN6/CTNNB1/CEACAM1 pathway of insulin internalization. Blocks anoikis of malignant kidney and intestinal epithelial cells and promotes their anchorage-independent growth by down-regulating DAPK2.<ref>PMID:17524503</ref> <ref>PMID:18086858</ref> <ref>PMID:18957423</ref> <ref>PMID:21262353</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The inhibition of intracellular protein-protein interactions is challenging, in particular, when involved interfaces lack pronounced cavities. The transcriptional co-activator protein and oncogene betaâcatenin is a prime example of such a challenging target. Despite extensive targeting efforts, available high-affinity binders comprise only large molecular weight Inhibitors. This hampers the further development of therapeutically useful compounds. Herein, we report the design of a considerably smaller peptidomimetic scaffold derived from the alpha-helical betaâcatenin-binding motif of Axin. Sequence maturation and bicyclization provided a stitched peptide with an unprecedented crosslink architecture. The binding mode and site were confirmed by a crystal structure. Further derivatization yielded a beta-catenin inhibitor with single-digit micromolar activity in a cell-based assay. This study sheds a light on how to design helix mimetics with reduced molecular weight thereby improving their biological activity.

Structure-Based Design of Bicyclic Helical Peptides That Target the Oncogene beta-Catenin.,Yeste-Vazquez A, Paulussen FM, Wendt M, Klintrot R, Schulte C, Wallraven K, van Gijzel L, Simeonov B, van der Gaag M, Gerber A, Maric HM, Hennig S, Grossmann TN Angew Chem Int Ed Engl. 2024 Aug 21:e202411749. doi: 10.1002/anie.202411749. PMID:39167026<ref>PMID:39167026</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8ru3" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Grossmann TN]]
[[Category: Hennig S]]
[[Category: Klintrot CIR]]
[[Category: Yeste Vazquez A]]