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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The tri-Trp pocket of CRBN shows 100% conservation in CRBN orthologs across animal and plant kingdoms.
“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
The IMiD binding to CRBN section describes a hydrophobic pocket lined by three tryptophans and says its surface groove is highly conserved across CRBN orthologues. Extended Data Figure 1 lists animal orthologues for the conservation analysis, but the copy does not establish 100% conservation or extend that finding to plants. (LLM, conf=0.89)
Experimental — accuracy not yet measuredThalidomide analogs bind CRBN and change its substrate selectivity so that it recruits, ubiquitinates, and degrades proteins including IKZF1, IKZF3, CK1α, and GSPT1.
“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]
The sections on IMiD binding and CRBN ligase function describe thalidomide analogs binding CRBN and promoting the targeting of IKZF1 and IKZF3 for degradation, with thalidomide less effective than lenalidomide and pomalidomide. The paper also describes a change in substrate recruitment, but the passages do not support the claim that CK1α or GSPT1 is recruited, ubiquitinated, or degraded. No page numbers are available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThalidomide, lenalidomide, and pomalidomide cause ubiquitination and proteasomal degradation of IKZF1 and IKZF3 by bringing a C2H2 zinc finger domain to CRBN, the substrate receptor of CRL4CRBN.
“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]
The 'CRBN functions as a DCAF' section identifies CRBN as a substrate receptor and reports IMiD-dependent degradation of IKZF1/3, noting that thalidomide is less efficient than lenalidomide and pomalidomide. The 'Thalidomide is an agonist and antagonist' section proposes recruitment of Ikaros to IMiD-bound CRBN but says the detailed binding mode remains to be established. Our copy does not identify a C2H2 zinc finger domain as the recruited portion, so that specific mechanism is unsupported. (LLM, conf=0.88)
Experimental — accuracy not yet measuredEarlier work implicated the second C2H2 zinc finger domain in IKZF1 and IKZF3, and ZF4 of ZFP91, as drug-inducible degrons.
“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]
The “CRBN functions as a DCAF for the CRL4CRBN ligase” section (page unavailable) reports drug-induced degradation of IKZF1 and IKZF3. It does not identify their second C2H2 zinc finger as a degron, and the searched passages do not address ZFP91 or its ZF4 domain. (LLM, conf=0.83)
Experimental — accuracy not yet measuredCRL4CRBN has a ubiquitination radius of approximately 100 Å.
“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]
In “CRBN functions as a DCAF for the CRL4CRBN ligase” (page unavailable), the paper describes a ubiquitination zone created by rotation of the ligase arm. It gives the zone’s dimensions as up to 340 × 110 × 30 Å, not a ubiquitination radius of approximately 100 Å. (LLM, conf=0.85)
Experimental — accuracy not yet measured
In 2014, landmark studies revealed that thalidomide and lenalidomide did not behave as inhibitors but functioned as molecular glue degraders analogous to auxin degrader TIR1.
“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
The paper’s Abstract and “Thalidomide is an agonist and antagonist” section describe IMiD-driven Ikaros/Aiolos degradation and explicitly compare the proposed mechanism with auxin-induced degradation by TIR1. But the claim’s contrast with inhibitors is too absolute: the paper also says IMiDs block recruitment of the endogenous substrate MEIS2. It describes lenalidomide as more effective than thalidomide at targeting Ikaros for degradation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThalidomide analogues bring zinc-finger transcription factors and other targets to CRBN, the substrate receptor of the CRL4CRBN E3 ligase.
“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]
The CRBN CTD contains the IMiD binding pocket formed by Trp380, Trp386, and Trp400, with Phe402 at its base.
“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
Compound 1 caused dose-dependent KAT2A degradation by western blot, and this degradation was rescued by MLN4924, bortezomib, and pomalidomide.
“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]
CUL4 can rotate up to 150° around DDB1, generating a large ubiquitylation zone spacious enough to allow CRBN autoubiquitylation without a substrate being present.
“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
IMiDs occupy a tryptophan cage binding site on CRBN with an affinity of ~150-250 nM.
“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]
Over a dozen proteins, including Ikaros, Aiolos, GSPT1, CK1α, glutamine synthetase, MEIS2, KCNMA1/SLO1, CLC1, and AMPKα, have been identified as substrates for CRBN.
“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]
The transcription factors Ikaros, Aiolos, and MEIS2 are localized to the nucleus.
“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]
GSPT1, CK1α, and glutamine synthetase reside in the cytoplasm.
“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]
Molecular glues constitute another important therapeutic class of targeted protein degraders.
“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]
All pharmacologically active derivatives of thalidomide contain a glutarimide ring that directly binds within a conserved pocket on the surface of CRBN.
“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]
Each target protein has been found to contain a structural degron composed of a β-hairpin with a pinnacle glycine motif, most often a C2H2 zinc finger domain, that binds to a composite thalidomide analogue-CRBN surface.
“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]
IMiDs, via their glutarimide moiety, become inserted into the tri-Trp pocket composed of three tryptophan residues (W380, W386, and W400) located at the C-terminus of CRBN.
“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]
Thalidomide displaces endogenous CRBN substrates such as MEIS2, perhaps explaining its teratogenic effects in pregnant women.
“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]
CRBN is a substrate recognition unit of the CUL4-RBX1-DDB1 E3 ligase complex.
“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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Medicinal chemistry updates of novel HDACs inhibitors (2020 to present)
He, X., Hui, Z., Xu, L., Bai, R., Gao, Y., Wang, Z., Xie, T., & Ye, X.-Y. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113946 · Cited by 89 · see citing works
Discovery of thalidomide-based PROTAC small molecules as the highly efficient SHP2 degraders
Yang, X., Wang, Z., Pei, Y., Song, N., Xu, L., Feng, B., Wang, H., Luo, X., Hu, X., Qiu, X., et al. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113341 · Cited by 85 · see citing works
UBE2G1 governs the destruction of cereblon neomorphic substrates
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UbiHub: a data hub for the explorers of ubiquitination pathways
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Drug resistance in multiple myeloma: Soldiers and weapons in the bone marrow niche
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Development of PDE6D and CK1α Degraders through Chemical Derivatization of FPFT-2216
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Self-citation
- 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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