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Peer-reviewedCC BYNature Chemical Biology

Dual E3 ligase recruitment by monovalent degraders for tunable SMARCA 2/4 degradation

  • Valentina A. Spiteri1
  • Dmitri Segal2,3
  • Alejandro Correa-Sáez1
  • Kentaro Iso1
  • Ryan Casement1
  • Miquel Muñoz i Ordoño2,3
  • Mark A. Nakasone1
  • Gajanan J. Sathe1
  • Caroline Schätz2,3
  • Hannah E. Peters1
  • Mark Dorward1
  • Lisa Kainacher2,3
3 more authors
  • Angus D. Cowan1
  • Alessio Ciulli4
  • Georg E. Winter5,6
6 affiliations
  1. 1Centre for Targeted Protein Degradation, School of Life Sciences, University of Dundee, Dundee, UK
  2. 2AITHYRA Research Institute for Biomedical Artificial Intelligence of the Austrian Academy of Sciences, Vienna, Austria
  3. 3CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
  4. 4Centre for Targeted Protein Degradation, School of Life Sciences, University of Dundee, Dundee, UK. [email protected]
  5. 5AITHYRA Research Institute for Biomedical Artificial Intelligence of the Austrian Academy of Sciences, Vienna, Austria. [email protected]
  6. 6CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. [email protected]
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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.

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Cite

BibTeXRIS
BibTeX
@article{spiteri2026dual,
  title = {{Dual E3 ligase recruitment by monovalent degraders for tunable SMARCA 2/4 degradation}},
  author = {Valentina A. Spiteri and Dmitri Segal and Alejandro Correa-Sáez and Kentaro Iso and Ryan Casement and Miquel Muñoz i Ordoño and Mark A. Nakasone and Gajanan J. Sathe and Caroline Schätz and Hannah E. Peters and Mark Dorward and Lisa Kainacher and Angus D. Cowan and Alessio Ciulli and Georg E. Winter},
  journal = {Nature Chemical Biology},
  year = {2026},
  month = may,
  doi = {10.1038/s41589-026-02224-y},
  url = {https://doi.org/10.1038/s41589-026-02224-y},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Dual E3 ligase recruitment by monovalent degraders for tunable SMARCA 2/4 degradation
AU  - Valentina A. Spiteri
AU  - Dmitri Segal
AU  - Alejandro Correa-Sáez
AU  - Kentaro Iso
AU  - Ryan Casement
AU  - Miquel Muñoz i Ordoño
AU  - Mark A. Nakasone
AU  - Gajanan J. Sathe
AU  - Caroline Schätz
AU  - Hannah E. Peters
AU  - Mark Dorward
AU  - Lisa Kainacher
AU  - Angus D. Cowan
AU  - Alessio Ciulli
AU  - Georg E. Winter
PY  - 2026
DA  - 2026/05/12
JO  - Nature Chemical Biology
DO  - 10.1038/s41589-026-02224-y
UR  - https://doi.org/10.1038/s41589-026-02224-y
AB  - 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.
SN  - 1552-4450
SN  - 1552-4469
ER  -