View source for 8eic


==Crystal structure of beta-catenin and the MDM2 p53-binding domain in complex with H330, a Helicon Polypeptide==
<StructureSection load='8eic' size='340' side='right'caption='[[8eic]], [[Resolution|resolution]] 2.62&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8eic]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8EIC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8EIC 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]] 2.62&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=WHL:~{N}-(4-acetamidophenyl)ethanamide'>WHL</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=8eic FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8eic OCA], [https://pdbe.org/8eic PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8eic RCSB], [https://www.ebi.ac.uk/pdbsum/8eic PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8eic 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 ==
Molecules that induce novel interactions between proteins hold great promise for the study of biological systems and the development of therapeutics, but their discovery has been limited by the complexities of rationally designing interactions between three components, and because known binders to each protein are typically required to inform initial designs. Here, we report a general and rapid method for discovering alpha-helically constrained (Helicon) polypeptides that cooperatively induce the interaction between two target proteins without relying on previously known binders or an intrinsic affinity between the proteins. We show that Helicons are capable of binding every major class of E3 ubiquitin ligases, which are of great biological and therapeutic interest but remain largely intractable to targeting by small molecules. We then describe a phage-based screening method for discovering "trimerizer" Helicons, and apply it to reprogram E3s to cooperatively bind an enzyme (PPIA), a transcription factor (TEAD4), and a transcriptional coactivator (beta-catenin).

Recognition and reprogramming of E3 ubiquitin ligase surfaces by alpha-helical peptides.,Tokareva OS, Li K, Travaline TL, Thomson TM, Swiecicki JM, Moussa M, Ramirez JD, Litchman S, Verdine GL, McGee JH Nat Commun. 2023 Nov 1;14(1):6992. doi: 10.1038/s41467-023-42395-z. PMID:37914719<ref>PMID:37914719</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8eic" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Synthetic construct]]
[[Category: Li K]]
[[Category: McGee JH]]
[[Category: Swiecicki J-M]]
[[Category: Thomson TM]]
[[Category: Tokareva OS]]
[[Category: Travaline TL]]
[[Category: Verdine GL]]