Molecular glue CELMoD compounds are regulators of cereblon conformation
Open accessAbstract
Cereblon (CRBN) is a ubiquitin ligase (E3) substrate receptor protein co-opted by CRBN E3 ligase modulatory drug (CELMoD) agents that target therapeutically relevant proteins for degradation. Prior crystallographic studies defined the drug-binding site within CRBN’s thalidomide-binding domain (TBD), but the allostery of drug-induced neosubstrate binding remains unclear. We performed cryo–electron microscopy analyses of the DNA damage-binding protein 1 (DDB1)–CRBN apo complex and compared these structures with DDB1-CRBN in the presence of CELMoD compounds alone and complexed with neosubstrates. Association of CELMoD compounds to the TBD is necessary and sufficient for triggering CRBN allosteric rearrangement from an open conformation to the canonical closed conformation. The neosubstrate Ikaros only stably associates with the closed CRBN conformation, illustrating the importance of allostery for CELMoD compound efficacy and informing structure-guided design strategies to improve therapeutic efficacy.
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E3 ubiquitin ligases natively adopt an open conformation in an apo state and have been observed only in a closed state when bound to ligands.
“E3 ubiquitin ligases natively adopt an open conformation in an apo state and have been observed only in a closed state when bound to ligands”
From Accurate structure prediction of biomolecular interactions with AlphaFold 3 (2024) · cites this paper as [42]
The paper’s Abstract reports an open apo-CRBN conformer, but it also reports ligand-bound CRBN in the open conformation. It explicitly says that ligand binding does not necessarily coincide with closure, contrary to the claim that ligand-bound complexes have been observed only in a closed state. The observations concern CRBN within a ligase complex, not E3 ubiquitin ligases generally. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredMGs bind to the C-terminal domain of cereblon and induce conformational changes that create a new surface interacting with zinc fingers containing a beta-turn CXXCG motif.
“With respect to the molecular glue-induced interaction of zinc finger transcription factors with cereblon, structural studies show that MGs bind to the C-terminal domain of cereblon and induce conformational changes that result in a new surface that interacts with zinc fingers containing a beta turn motif with sequence CXXCG7–9.”
From Structural and biophysical comparisons of the pomalidomide- and CC-220-induced interactions of SALL4 with cereblon (2023) · cites this paper as [7]
The indexed text (section labeled Abstract; page unavailable) says CELMoD compounds bind cereblon’s C-terminal thalidomide-binding domain and trigger an allosteric rearrangement. It also reports that an Ikaros zinc-finger motif associates with the resulting closed conformation. It does not identify the interacting motif as a beta-turn with the sequence CXXCG. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIt is the third binding mode for ZFs to CRBN:MG complexes.
“Additionally, it is the third binding mode for ZFs to CRBN:MG complexes adding to our understanding of the binding of single zinc fingers such as IKZF13,7 and ZNF6923, and the binding of two zinc fingers including C-terminal ancillary ZF3 in the IKZF2 ZF2-3 complex9,10.”
From Structural and biophysical comparisons of the pomalidomide- and CC-220-induced interactions of SALL4 with cereblon (2023) · cites this paper as [7]
The passage on Ikaros recruitment (section labeled Abstract; page unavailable) supports binding of a single zinc-finger motif to a molecular-glue-bound CRBN complex. It does not establish a third binding mode or describe an IKZF2 ZF2–3 complex with an ancillary ZF3, so those details are not supported by this source. (LLM, conf=0.82)
Experimental — accuracy not yet measuredKAT2ANTD buries a substantial portion of both CRBNNTD and CRBNCTD, forming a broad PPI distinct from the more hotspot-driven interfaces of G-loop neo-substrates, the G-loop mimetic, and the non-G-loop G3BP2.
“We found that KAT2ANTD buries a substantial portion of both the CRBNNTD and CRBNCTD, forming a broad PPI that is distinct from the more hotspot-driven interfaces created by the G-loop neo-substrates (e.g., IKZF1(45), GSPT1(40)), the G-loop mimetic (VAV1(11)), and the non-G-loop (G3BP2(14)) (Fig 3F).”
From Degron-independent recruitment of KAT2A expands the target space of CRBN molecular glues (2026) · cites this paper as [45]
In allosteric MGD function, the small molecule does not participate directly in the interaction; rather, it exposes or modifies a PPI interface by binding to a distant pocket that stabilizes a (non-native) conformation of the protein.
“In this case, the small molecule does not participate directly in the interaction. Rather, it exposes or modifies a PPI interface by binding to a distant pocket that stabilizes a (non-native) conformation of the protein.”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [260]
MGDs may also function from an allosteric site.
“Finally, MGDs may also function from an allosteric site.260”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [260]
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Accurate structure prediction of biomolecular interactions with AlphaFold 3
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“For example, E3 ubiquitin ligases natively adopt an open conformation in an apo state and have been observed only in a closed state when bound to ligands, but AF3 exclusively predicts the closed state for both holo and apo systems 42 (Fig.”
BackgroundFrom Thalidomide to Rational Molecular Glue Design for Targeted Protein Degradation
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“Additionally, it is the third binding mode for ZFs to CRBN:MG complexes adding to our understanding of the binding of single zinc fingers such as IKZF1 3,7 and ZNF692 3 , and the binding of two zinc fingers including C-terminal ancillary ZF3 in the IKZF2 ZF2-3 complex 9,10 .”
BackgroundIdentification of an allosteric site on the E3 ligase adapter cereblon
Dippon, V. N., Rizvi, Z., Choudhry, A. E., Chung, C.-W., Alkuraya, I. F., Xu, W., Tao, X. B., Jurewicz, A. J., Schneck, J. L., Chen, W., et al. (2026) · Nature · doi:10.1038/s41586-025-09994-w · Cited by 14 · see citing works
Self-citationCereblon induces G3BP2 neosubstrate degradation using molecular surface mimicry
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“Using the predicted CRBN surface patch to guide the creation of a ternary complex docking model (Methods) resulted in an overall compatible orientation of the G3BP2 NTF2L homodimer with the closed conformation of CRBN 24 (Extended Data Fig.”
Degron-independent recruitment of KAT2A expands the target space of CRBN molecular glues
Ojeda, S., Wang, M., Baek, K., Bourgeois, W., Sommerschield, A., Yue, H., Metivier, R. J., Karagiannis, P., Levitz, T. S., Xiong, Y., et al. (2026) · Science · doi:10.1126/science.aef5391 · Cited by 5 · see citing works
- Authors
- Watson, E. R., Novick, S., Matyskiela, M. E., Chamberlain, P. P., H. de la Peña, A., Zhu, J., Tran, E., Griffin, P. R., Wertz, I. E., & Lander, G. C.
- Affiliations
- Scripps Research Institute (US)
- University of Florida (US)
- Bristol-Myers Squibb (United States) (US)
- Bristol-Myers Squibb, San Diego, CA 92121, USA.
- Corresponding author
- Lander, Gabriel C.
- ORCID
- Venue
- Science
- Published
- 2022-11-04
- Volume
- 378
- Issue
- 6619
- Pages
- 549-553
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC9714526
- OpenAlex
- W4308439092
- Cited by
- 208
- References
- 31
- Citations by year
- 2026: 58 · 2025: 76 · 2024: 47 · 2023: 27
- FWCI
- 12.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1s10od021634-01)
- 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
- cereblon, allosteric regulation, protein conformational change, Ikaros, structure-based drug design, protein degradation
- MeSH terms
- Protein Domains, Allosteric Regulation, Thalidomide, Cryoelectron Microscopy, Ubiquitin-Protein Ligases, Adaptor Proteins, Signal Transducing
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