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Structure of the DDB1–CRBN E3 ubiquitin ligase in complex with thalidomide
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In the 1950s, the drug thalidomide, administered as a sedative to pregnant women, led to the birth of thousands of children with multiple defects. Despite the teratogenicity of thalidomide and its derivatives lenalidomide and pomalidomide, these immunomodulatory drugs (IMiDs) recently emerged as effective treatments for multiple myeloma and 5q-deletion-associated dysplasia. IMiDs target the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as CRL4(CRBN)) and promote the ubiquitination of the IKAROS family transcription factors IKZF1 and IKZF3 by CRL4(CRBN). Here we present crystal structures of the DDB1-CRBN complex bound to thalidomide, lenalidomide and pomalidomide. The structure establishes that CRBN is a substrate receptor within CRL4(CRBN) and enantioselectively binds IMiDs. Using an unbiased screen, we identified the homeobox transcription factor MEIS2 as an endogenous substrate of CRL4(CRBN). Our studies suggest that IMiDs block endogenous substrates (MEIS2) from binding to CRL4(CRBN) while the ligase complex is recruiting IKZF1 or IKZF3 for degradation. This dual activity implies that small molecules can modulate an E3 ubiquitin ligase and thereby upregulate or downregulate the ubiquitination of proteins.
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“These residues form a small hydrophobic pocket (tri-Trp pocket), which shows 100% conservation in CRBN orthologs across animal and plant kingdoms (Chamberlain et al., 2014; Fischer et al., 2014) (Figure S7A).”
From Glutamine Triggers Acetylation-Dependent Degradation of Glutamine Synthetase via the Thalidomide Receptor Cereblon (2016) · cites this paper as Fischer et al., 2014
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Thalidomide analogs bind Cereblon (CRBN), the substrate receptor of the CUL4-RBX1-DDB1-CRBN (CRL4CRBN) E3 ubiquitin ligase and alter its substrate selectivity to recruit, ubiquitinate and degrade seemingly unrelated proteins including Ikaros (IKZF1), Aiolos (IKZF3), Casein kinase 1 alpha (CK1α) and GSPT1 (2–7).”
From Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN (2018) · cites this paper as [7]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The small molecules thalidomide, lenalidomide, and pomalidomide induce the ubiquitination and proteasomal degradation of the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) by recruiting a Cys2-His2 (C2H2) zinc finger domain to Cereblon (CRBN), the substrate receptor of the CRL4CRBN E3 ubiquitin ligase.”
From Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN (2018) · cites this paper as [7]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Previous work has implicated the second C2H2 ZF domain in IKZF1 and IKZF3 (5, 7), and ZF4 of ZFP91 as the drug-inducible degrons (5, 7, 16).”
From Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN (2018) · cites this paper as [7]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Given the CRL4CRBN protein architecture and its ~100 Å ubiquitination radius (6, 7, 22)”
From Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN (2018) · cites this paper as [7]
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“the second breakthrough came in 2014 when a series of landmark studies revealed that thalidomide, and its more potent derivative lenalidomide, did not behave as inhibitors but in fact functioned as molecular glue degraders analogous to the auxin degrader tiR1 (chamberlain et al. 2014;Fischer et al. 2014;gandhi et al. 2014;Krönke et al. 2014;lu et al. 2014).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Fischer et al. 2014
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“Thalidomide analogues recruit zinc-finger transcription factors and other targets to CRBN8–11, the substrate receptor of the cullin-RING E3 ubiquitin ligase CUL4A/B-RBX1-DDB1-CRBN (CRL4CRBN)12.”
From The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K (2020) · cites this paper as [12]
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“The CTD harbors the IMiD binding pocket formed by Trp380, Trp386 and Trp400, with a phenylalanine residue at the base (Phe402) (Chamberlain et al., 2014; Fischer et al., 2014).”
From Glutamine Triggers Acetylation-Dependent Degradation of Glutamine Synthetase via the Thalidomide Receptor Cereblon (2016) · cites this paper as Fischer et al., 2014
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“orthogonally confirmed dose-dependent KAT2A degradation by western blot, and demonstrated that this degradation can be rescued by pre-treatment with a UBA3/NAE1 inhibitor, MLN4924 (37), a proteasome inhibitor, bortezomib (38), and a competing CRBN ligand, pomalidomide (7) (Fig. 1D).”
From Degron-independent recruitment of KAT2A expands the target space of CRBN molecular glues (2026) · cites this paper as [7]
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“Structural studies show that cul4 can rotate up to 150° around DDB1, the cRBN adaptor, generating a large ubiquitylation zone spacious enough to allow cRBN autoubiquitylation without a substrate being present (Zimmerman et al. 2010;Fischer et al. 2014).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Fischer et al. 2014
In the citing paper
“Previous studies have shown that IMiDs can occupy a tryptophan cage binding site on CRBN with an affinity of ~150–250 nM35.”
From Defining molecular glues with a dual-nanobody cannabidiol sensor (2022) · cites this paper as [35]
In the citing paper
“To date, over a dozen proteins including Ikaros, Aiolos, GSPT1, CK1α, glutamine synthetase, MEIS2, KCNMA1/SLO1, CLC1, and AMPKα have been identified as substrates for CRBN3,11–16,24–28.”
From Genome-wide screening reveals a role for subcellular localization of CRBN in the anti-myeloma activity of pomalidomide (2020) · cites this paper as [25]
In the citing paper
“The subcellular localizations of these factors differ: the transcription factors Ikaros, Aiolos, and MEIS2 are localized to the nucleus, whereas GSPT1, CK1α, and glutamine synthetase reside in the cytoplasm.”
From Genome-wide screening reveals a role for subcellular localization of CRBN in the anti-myeloma activity of pomalidomide (2020) · cites this paper as [25]
In the citing paper
“The subcellular localizations of these factors differ: the transcription factors Ikaros, Aiolos, and MEIS2 are localized to the nucleus, whereas GSPT1, CK1α, and glutamine synthetase reside in the cytoplasm.”
From Genome-wide screening reveals a role for subcellular localization of CRBN in the anti-myeloma activity of pomalidomide (2020) · cites this paper as [25]
In the citing paper
“Molecular glues, based on the serendipitous discovery that thalidomide and its analogues act as degrader molecules, constitute another important therapeutic class1–8.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [7]
In the citing paper
“All pharmacologically active derivatives of thalidomide contain a glutarimide ring that directly binds within a conserved pocket on the surface of CRBN17”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [17]
In the citing paper
“Each target protein has been found to contain a structural degron composed of a β-hairpin with a pinnacle glycine motif, most often in the form of a Cys2-His2 (C2H2) zinc finger domain, that binds to a composite thalidomide analogue–CRBN surface17,117,121,167.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [17]
In the citing paper
“Both groups concluded that IMiDs, via their glutarimide moiety, become inserted into the tripletryptophan (tri-Trp) pocket composed of three tryptophan residues (W380, W386, and W400) located at the C-teminus of CRBN.”
From Cereblon and its downstream substrates as molecular targets of immunomodulatory drugs (2016) · cites this paper as [33]
In the citing paper
“However, thalidomide displaces endogenous CRBN substrates, such as the transcription factor MEIS2 which is involved in embryonic development, perhaps explaining its teratogenic effects in pregnant women [69, 73–75].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [69]
In the citing paper
“CRBN is a substrate recognition unit of the CUL4–RBX1–DDB1 E3 ligase complex [69].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [69]
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Metadata
- Authors
- Fischer, E. S., Böhm, K., Lydeard, J. R., Yang, H., Stadler, M. B., Cavadini, S., Nagel, J., Serluca, F., Acker, V., Lingaraju, G. M., Tichkule, R. B., Schebesta, M., Forrester, W. C., Schirle, M., Hassiepen, U., Ottl, J., Hild, M., Beckwith, R. E. J., Harper, J. W., Jenkins, J. L., & Thomä, N. H.
- Affiliations
- University of Basel (CH)
- Harvard University (US)
- Novartis (Switzerland) (CH)
- Corresponding author
- Thomä, Nicolas H.
- ORCID
- Venue
- Nature
- Published
- 2014-07-16
- Volume
- 512
- Issue
- 7512
- Pages
- 49-53
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4423819
- OpenAlex
- W2161413435
- Cited by
- 1,141
- References
- 44
- Citations by year
- 2026: 130 · 2025: 159 · 2024: 130 · 2023: 103 · 2022: 119 · 2021: 98 · 2020: 109 · 2019: 76 · 2018: 63 · 2017: 52 · 2016: 54 · 2015: 35 · 2014: 12
- FWCI
- 21.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DORA PSI (Paul Scherrer Institute) (submittedVersion)
- Funders
- National Institute on Aging (AG011085, R01AG011085)
- 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
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Keywords
- thalidomide, lenalidomide, pomalidomide, immunomodulators, E3 ubiquitin ligase, enantioselective binding, MEIS2, IKZF1, IKZF3, multiple myeloma
- MeSH terms
- Lenalidomide, DNA-Binding Proteins, Humans, Models, Molecular, Peptide Hydrolases, Protein Binding, Structure-Activity Relationship, Substrate Specificity, Thalidomide, Transcription Factors, Crystallography, X-Ray, Homeodomain Proteins, Ubiquitin-Protein Ligases, Multiprotein Complexes, Adaptor Proteins, Signal Transducing
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