6m94
From Proteopedia
Monophosphorylated pSer33 b-Catenin peptide bound to b-TrCP/Skp1 Complex
Structural highlights
FunctionSKP1_HUMAN Essential component of the SCF (SKP1-CUL1-F-box protein) ubiquitin ligase complex, which mediates the ubiquitination of proteins involved in cell cycle progression, signal transduction and transcription. In the SCF complex, serves as an adapter that links the F-box protein to CUL1. SCF(BTRC) mediates the ubiquitination of NFKBIA at 'Lys-21' and 'Lys-22'; the degradation frees the associated NFKB1-RELA dimer to translocate into the nucleus and to activate transcription. SCF(Cyclin F) directs ubiquitination of CP110.[1] [2] Publication Abstract from PubMedProtein-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[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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