7ar4
Crystal structure of beta-catenin in complex with cyclic peptide inhibitor
Structural highlights
DiseaseCTNB1_HUMAN Defects in CTNNB1 are associated with colorectal cancer (CRC) [MIM: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:132600; a common benign skin tumor.[1] [2] [3] Defects in CTNNB1 are a cause of medulloblastoma (MDB) [MIM:155255. MDB is a malignant, invasive embryonal tumor of the cerebellum with a preferential manifestation in children.[4] [5] Defects in CTNNB1 are a cause of susceptibility to ovarian cancer (OC) [MIM: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: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.[6] FunctionCTNB1_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.[7] [8] [9] [10] Publication Abstract from PubMedProtein complexes are defined by the three-dimensional structure of participating binding partners. Knowledge about these structures can facilitate the design of peptidomimetics which have been applied for example, as inhibitors of protein-protein interactions (PPIs). Even though beta-sheets participate widely in PPIs, they have only rarely served as the basis for peptidomimetic PPI inhibitors, in particular when addressing intracellular targets. Here, we present the structure-based design of beta-sheet mimetics targeting the intracellular protein beta-catenin, a central component of the Wnt signaling pathway. Based on a protein binding partner of beta-catenin, a macrocyclic peptide was designed and its crystal structure in complex with beta-catenin obtained. Using this structure, we designed a library of bicyclic beta-sheet mimetics employing a late-stage diversification strategy. Several mimetics were identified that compete with transcription factor binding to beta-catenin and inhibit Wnt signaling in cells. The presented design strategy can support the development of inhibitors for other beta-sheet-mediated PPIs. Bicyclic beta-Sheet Mimetics that Target the Transcriptional Coactivator beta-Catenin and Inhibit Wnt Signaling.,Wendt M, Bellavita R, Gerber A, Efrem NL, van Ramshorst T, Pearce NM, Davey PRJ, Everard I, Vazquez-Chantada M, Chiarparin E, Grieco P, Hennig S, Grossmann TN Angew Chem Int Ed Engl. 2021 Jun 14;60(25):13937-13944. doi: , 10.1002/anie.202102082. Epub 2021 May 5. PMID:33783110[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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