6M93

Monophosphorylated pSer33 b-Catenin peptide, b-TrCP/Skp1, NRX-1933 ternary complex

Summary for 6M93

• Entry DOI: 10.2210/pdb6m93/pdb
• Descriptor: F-box/WD repeat-containing protein 1A, S-phase kinase-associated protein 1, Catenin beta-1, ... (6 entities in total)
• Functional Keywords: ubiquitin molecular glue enhancer, ligase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 69868.10

Authors

Simonetta, K.R.,Clifton, M.C.,Walter, R.L.,Ranieri, G.M.,Lee, S.J. (deposition date: 2018-08-22, release date: 2019-04-03, Last modification date: 2024-10-09)

Primary citation

Simonetta, K.R.,Taygerly, J.,Boyle, K.,Basham, S.E.,Padovani, C.,Lou, Y.,Cummins, T.J.,Yung, S.L.,von Soly, S.K.,Kayser, F.,Kuriyan, J.,Rape, M.,Cardozo, M.,Gallop, M.A.,Bence, N.F.,Barsanti, P.A.,Saha, A.
Prospective discovery of small molecule enhancers of an E3 ligase-substrate interaction.
Nat Commun, 10:1402-1402, 2019

PubMed Abstract: 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, β-Catenin, and its cognate E3 ligase, SCF. These enhancers potentiate the ubiquitylation of mutant β-Catenin by β-TrCP in vitro and induce the degradation of an engineered mutant β-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.

PubMed: 30926793
DOI: 10.1038/s41467-019-09358-9

Experimental method

X-RAY DIFFRACTION (2.5 Å)