2026/05/12 by Valentina A. Spiteri, Dmitri Segal, Alejandro Correa-Sáez +12 · 1 voice
Biochemistry, Genetics and Molecular Biology · Chemistry · #Chromatin Remodeling and Cancer #Click Chemistry and Applications #Protein Degradation and Inhibitors
paper · doi:10.1038/s41589-026-02224-y
openalex publication_date 2026/05/12 · openalex created_date 2026/05/13 · openalex updated_date 2026/07/29
Abstract Proteolysis-targeting chimeras (PROTACs) and molecular glue degraders (MGDs) target proteins for degradation by co-opting an E3 ligase. While heterotrivalent PROTACs that can recruit multiple E3 ligases have been described, all MGDs reported to date depend on a single E3. Using orthogonal genetic screening, biophysical and structural analyses, we show that a monovalent MGD can recruit CUL4 DCAF16 and CRL1 FBXO22 in parallel to degrade SMARCA2/4. Deep mutational scanning identifies C173 in DCAF16 as essential for degrader activity and intact protein mass spectrometry confirms covalent modification at this site. Elucidating the ternary complex structure reveals a unique binding mode and a distinct interface of neointeractions that underlie degrader specificity. We demonstrate that ligase dependency is chemically and genetically tunable. Minimal compound modifications shift preference from DCAF16 to FBXO22, while a single substitution boosts degrader dependency on DCAF16. These results establish a framework for designing tunable dual E3 ligase degraders to mitigate potential resistance mechanisms.