6m91

Monophosphorylated pSer33 b-Catenin peptide, b-TrCP/Skp1, NRX-103094 ternary complex

spinqualitylabelsall models 6m91, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6m91 is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.4Å Ligands: CL, J97, PO4, SEP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function FBW1A_HUMAN Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Recognizes and binds to phosphorylated target proteins. SCF(BTRC) mediates the ubiquitination of CTNNB1 and participates in Wnt signaling. SCF(BTRC) mediates the ubiquitination of NFKBIA, NFKBIB and NFKBIE; the degradation frees the associated NFKB1 to translocate into the nucleus and to activate transcription. Ubiquitination of NFKBIA occurs at 'Lys-21' and 'Lys-22'. SCF(BTRC) mediates the ubiquitination of phosphorylated NFKB1/nuclear factor NF-kappa-B p105 subunit, ATF4, SMAD3, SMAD4, CDC25A, DLG1, FBXO5 and probably NFKB2. SCF(BTRC) mediates the ubiquitination of phosphorylated SNAI1. May be involved in ubiquitination and subsequent proteasomal degradation through a DBB1-CUL4 E3 ubiquitin-protein ligase. Required for activation of NFKB-mediated transcription by IL1B, MAP3K14, MAP3K1, IKBKB and TNF. Required for proteolytic processing of GLI3. Publication Abstract from PubMed Protein-protein interactions (PPIs) governing the recognition of substrates by E3 ubiquitin ligases are critical to cellular function. There is significant therapeutic potential in the development of small molecules that modulate these interactions; however, rational design of small molecule enhancers of PPIs remains elusive. Herein, we report the prospective identification and rational design of potent small molecules that enhance the interaction between an oncogenic transcription factor, beta-Catenin, and its cognate E3 ligase, SCF(beta-TrCP). These enhancers potentiate the ubiquitylation of mutant beta-Catenin by beta-TrCP in vitro and induce the degradation of an engineered mutant beta-Catenin in a cellular system. Distinct from PROTACs, these drug-like small molecules insert into a naturally occurring PPI interface, with contacts optimized for both the substrate and ligase within the same small molecule entity. The prospective discovery of 'molecular glue' presented here provides a paradigm for the development of small molecule degraders targeting hard-to-drug proteins. Prospective discovery of small molecule enhancers of an E3 ligase-substrate interaction.,Simonetta KR, Taygerly J, Boyle K, Basham SE, Padovani C, Lou Y, Cummins TJ, Yung SL, von Soly SK, Kayser F, Kuriyan J, Rape M, Cardozo M, Gallop MA, Bence NF, Barsanti PA, Saha A Nat Commun. 2019 Mar 29;10(1):1402. doi: 10.1038/s41467-019-09358-9. PMID:30926793 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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