9S3R
Ternary complex structure of compound 1 bound to SMARCA2 bromodomain and DCAF16:DDB1deltaBPB
This is a non-PDB format compatible entry.
Summary for 9S3R
| Entry DOI | 10.2210/pdb9s3r/pdb |
| EMDB information | 54549 |
| Descriptor | DNA damage-binding protein 1, DDB1- and CUL4-associated factor 16, Probable global transcription activator SNF2L2, ... (6 entities in total) |
| Functional Keywords | protein complex, covalent degrader, targeted protein degradation, transcription, e3 ligase |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 178243.83 |
| Authors | Spiteri, V.A.,Nakasone, M.A.,Casement, R.,Iso, K.,Cowan, A.D.,Ciulli, A. (deposition date: 2025-07-25, release date: 2026-05-20, Last modification date: 2026-05-27) |
| Primary citation | Spiteri, V.A.,Segal, D.,Correa-Saez, A.,Iso, K.,Casement, R.,Munoz I Ordono, M.,Nakasone, M.A.,Sathe, G.,Schatz, C.,Peters, H.E.,Doward, M.,Kainacher, L.,Cowan, A.D.,Ciulli, A.,Winter, G.E. Dual E3 ligase recruitment by monovalent degraders for tunable SMARCA 2/4 degradation. Nat.Chem.Biol., 2026 Cited by PubMed 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 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. PubMed: 42120501DOI: 10.1038/s41589-026-02224-y PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.3 Å) |
Structure validation
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