Dual E3 ligase recruitment by monovalent degraders for tunable SMARCA 2/4 degradation
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.
Authors
- Georg E. Winter (ORCID: https://orcid.org/0000-0001-6606-1437)
- Dmitri Segal (ORCID: https://orcid.org/0000-0003-0880-4794)
- Ryan Casement (ORCID: https://orcid.org/0000-0002-5008-9491)
- Valentina A. Spiteri (ORCID: https://orcid.org/0000-0002-5002-4989)
- Kentaro Iso (ORCID: https://orcid.org/0000-0001-5417-3642)
- Alejandro Correa-Sáez (ORCID: https://orcid.org/0000-0001-5240-4865)
- Angus D. Cowan (ORCID: https://orcid.org/0000-0002-9702-7319)
- Mark A. Nakasone (ORCID: https://orcid.org/0000-0002-1362-191X)
- Mark Doward
- Lisa Kainacher
- Gajanan Sathe (ORCID: https://orcid.org/0000-0002-6239-5365)
- Miquel Muñoz i Ordoño (ORCID: https://orcid.org/0009-0003-4391-6393)
- Hannah E. Peters
- Alessio Ciulli (ORCID: https://orcid.org/0000-0002-8654-1670)
- Caroline Schätz (ORCID: https://orcid.org/0000-0002-8391-8778)
Institutions
- Austrian Academy of Sciences (AT)
- University of Dundee (GB)
- CeMM Research Center for Molecular Medicine (AT)
- AITHYRA GmbH- Research Institute for Biomedical Artificial Intelligence (Austria) (AT)
Publication Details
- Journal
- Nature Chemical Biology
- Published
- 2026-05-12
- DOI
- https://doi.org/10.1038/s41589-026-02224-y
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 0.00