Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15
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Abstract
The investigational drugs E7820, indisulam and tasisulam (aryl-sulfonamides) promote the degradation of the splicing factor RBM39 in a proteasome-dependent mechanism. While the activity critically depends on the cullin RING ligase substrate receptor DCAF15, the molecular details remain elusive. Here we present the cryo-EM structure of the DDB1-DCAF15-DDA1 core ligase complex bound to RBM39 and E7820 at a resolution of 4.4 Å, together with crystal structures of engineered subcomplexes. We show that DCAF15 adopts a new fold stabilized by DDA1, and that extensive protein-protein contacts between the ligase and substrate mitigate low affinity interactions between aryl-sulfonamides and DCAF15. Our data demonstrate how aryl-sulfonamides neo-functionalize a shallow, non-conserved pocket on DCAF15 to selectively bind and degrade RBM39 and the closely related splicing factor RBM23 without the requirement for a high-affinity ligand, which has broad implications for the de novo discovery of molecular glue degraders.
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Aryl sulphonamides degrade RBM39 by engaging DCAF15, the substrate receptor of the CRL4DCAF15 E3 ligase.
“Similarly, aryl sulphonamides degrade the essential RNA-binding protein RBM39 by engaging DCAF15, the substrate receptor of the CRL4DCAF15 E3 ubiquitin ligase13–15.”
From The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K (2020) · cites this paper as [15]
The same MG mechanism has been revealed for antitumor aryl-sulfonamides, which reprogram DCAF15 to bind and degrade certain RNA-binding proteins.
“The same MG mechanism has subsequently been revealed for antitumor aryl-sulfonamides, which reprograms another CRL4 substrate receptor, DCAF15, to bind and degrade certain RNA-binding proteins21–26.”
From Defining molecular glues with a dual-nanobody cannabidiol sensor (2022) · cites this paper as [25]
Additional MGDs have been reported that induce degradation of proteins devoid of obvious ligand-binding pockets, such as RBM39 or cyclin K.
“Additional MGDs have been reported, which induce the degradation of proteins devoid of obvious ligand-binding pockets, such as RBM3954−57 or cyclin K (CycK).58−60”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [56]
Comparative chemical screening of hyponeddylated and well-neddylated cell lines revealed three destabilizers of cyclin K.
“Secondly, comparative chemical screening of hyponeddylated and well-neddylated cell lines revealed three destabilizers of cyclin K183.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [183]
Two additional, entirely distinct classes of small-molecule molecular glue degraders have been discovered.
“Two additional, entirely distinct classes of small-molecule molecular glue degraders have been discovered.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [183]
Three independent chemogenomic screening studies identified structurally diverse molecular glue degraders of cyclin K.
“With regard to the second novel class of agents, three independent chemogenomic screening studies resulted in the identification of structurally diverse molecular glue degraders of cyclin K.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [183]
Structurally divergent small molecules all directly engage a substrate receptor-less CUL4 E3 ligase complex by binding to DDB1 while interacting with and recruiting CDK12 in complex with cyclin K.
“Remarkably, these structurally divergent small molecules all directly engage a substrate receptor-less CUL4 E3 ligase complex by binding to its substrate adaptor component, DDB1, whilst simultaneously interacting with and thereby recruiting CDK12 in complex with cyclin K.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [183]
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- Authors
- Faust, T. B., Yoon, H., Nowak, R. P., Donovan, K. A., Li, Z., Cai, Q., Eleuteri, N. A., Zhang, T., Gray, N. S., & Fischer, E. S.
- Affiliations
- Harvard University (US)
- Corresponding author
- Fischer, Eric S.
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2019-11-04
- Volume
- 16
- Issue
- 1
- Pages
- 7-14
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC6917914
- OpenAlex
- W2985294481
- Cited by
- 218
- References
- 44
- Citations by year
- 2026: 19 · 2025: 30 · 2024: 39 · 2023: 28 · 2022: 33 · 2021: 31 · 2020: 37 · 2019: 1
- FWCI
- 8.52
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Nature Chemical Biology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (1F32CA232772-01, R01CA214608)
- Damon Runyon Cancer Research Foundation (DRR-50-18)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- RBM39, DCAF15, cullin-RING ligases, arylsulfonamides, molecular glues, proteasomal degradation, protein-protein interaction, binding pocket, cryo-EM structure
- MeSH terms
- RNA Recognition Motif Proteins, Protein Domains, Animals, Benzamides, Humans, Indoles, Kinetics, Protein Binding, Sulfonamides, Xenopus, RNA-Binding Proteins, Protein Structure, Secondary, Spodoptera, Cryoelectron Microscopy, Amino Acid Motifs, Protein Interaction Mapping, Fluorescence Resonance Energy Transfer, Ubiquitin-Protein Ligases, Intracellular Signaling Peptides and Proteins, Receptors, Interleukin-17, Proteolysis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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