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TitleDual E3 ligase recruitment by monovalent degraders for tunable SMARCA 2/4 degradation.
Journal, issue, pagesNat Chem Biol, Year 2026
Publish dateMay 12, 2026
AuthorsValentina A Spiteri / Dmitri Segal / Alejandro Correa-Sáez / Kentaro Iso / Ryan Casement / Miquel Muñoz I Ordoño / Mark A Nakasone / Gajanan Sathe / Caroline Schätz / Hannah E Peters / Mark Doward / Lisa Kainacher / Angus D Cowan / Alessio Ciulli / Georg E Winter /
PubMed AbstractProteolysis-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 ...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 and CRL1 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.
External linksNat Chem Biol / PubMed:42120501
MethodsEM (single particle)
Resolution3.3 Å
Structure data

54549

9s3r

EMDB-54549, PDB-9s3r:
Ternary complex structure of compound 1 bound to SMARCA2 bromodomain and DCAF16:DDB1deltaBPB
Method: EM (single particle) / Resolution: 3.3 Å

Chemicals

ChemComp-ZN:
Unknown entry

PDB-1jlv:
Anopheles dirus species B glutathione S-transferases 1-3

Source
  • homo sapiens (human)
KeywordsTRANSCRIPTION / Protein complex / covalent degrader / targeted protein degradation / E3 ligase

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