Plasticity in binding confers selectivity in ligand-induced protein degradation
Open accessAbstract
Heterobifunctional small-molecule degraders that induce protein degradation through ligase-mediated ubiquitination have shown considerable promise as a new pharmacological modality. However, we currently lack a detailed understanding of the molecular basis for target recruitment and selectivity, which is critically required to enable rational design of degraders. Here we utilize a comprehensive characterization of the ligand-dependent CRBN-BRD4 interaction to demonstrate that binding between proteins that have not evolved to interact is plastic. Multiple X-ray crystal structures show that plasticity results in several distinct low-energy binding conformations that are selectively bound by ligands. We demonstrate that computational protein-protein docking can reveal the underlying interprotein contacts and inform the design of a BRD4 selective degrader that can discriminate between highly homologous BET bromodomains. Our findings that plastic interprotein contacts confer selectivity for ligand-induced protein dimerization provide a conceptual framework for the development of heterobifunctional ligands.
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Linker length plays an important role in PROTAC potency.
“The length of linker plays an important role in the potency of PROTAC molecules[29,30].”
From Development of MDM2 degraders based on ligands derived from Ugi reactions: Lessons and discoveries (2021) · cites this paper as [29]
It is widely believed that degraders uncouple efficacy from target occupancy.
“It is widely believed that degraders uncouple efficacy from target occupancy (Gadd et al., 2017; Nowak et al., 2018; Olson et al., 2018; Roy et al., 2019).”
From Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development (2020) · cites this paper as Nowak et al., 2018
Changes to linker length can significantly alter the selectivity profile of degraders, such as transforming a pan-BET degrader to a BRD4 selective degrader.
“Changes to linker length have proven to significantly alter the selectivity profile of degraders, such as the transformation of a pan-BET degrader to a BRD4 selective degrader (Nowak et al., 2018).”
From Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development (2020) · cites this paper as Nowak et al., 2018
In 2018, Nowak et al. applied in silico protein-protein docking frameworks to identify low-energy binding modes that guided design of BRD4 selective PROTACs.
“In 2018, Nowak et al. applied in silico protein-protein docking frameworks to identify low-energy binding modes that guided the design of BRD4 selective PROTACs.42”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [42]
DD-04-118 differs from DD-03-171 by a single atom change of the thalidomide aryl amine nitrogen to an oxygen, predicted to compromise its ability to recruit IKZF1/3 to CRBN.
“We also generated DD-04-118 (Figure 1A), an analog which differs from DD-03-171 by only a single atom change of the thalidomide aryl amine nitrogen to an oxygen, resulting in an aryl ether, a change that was predicted to compromise its ability to recruit IKZF1/3 to CRBN.22”
From Bruton tyrosine kinase degradation as a therapeutic strategy for cancer (2019) · cites this paper as [22]
A BRD4 degrader achieves selectivity versus BRD2 and BRD3 by exploiting structural differences in the bromodomain/E3 ligase protein-protein interface.
“We also developed a BRD4 degrader that achieves selectivity versus BRD2 and BRD3 by exploiting structural differences in the bromodomain/E3 ligase protein-protein interface[10].”
From Development of dual and selective degraders of cyclin-dependent kinases 4 and 6 (2019) · cites this paper as [10]
Many single-point mutations to either Brd4 or CRBN outside their ligand-binding sites lead to modest changes that enhance or reduce ternary complex formation, without finding mutations that abrogate the interaction completely.
“It is further consistent with the fact that many single-point mutations to either Brd4 or to CRBN (outside of their respective ligand-binding sites) lead to modest changes that enhance or reduce ternary complex formation, without finding mutations that abrogate the interaction completely 54.”
From Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta (2021) · cites this paper as [54]
There are not yet enough published crystal structures of ternary complexes to allow for a thorough and rigorous evaluation of the method.
“While there have been several published crystal structures of ternary complexes 35, 52, 54, there are not yet enough to allow for a thorough and rigorous evaluation of our method.”
From Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta (2021) · cites this paper as [54]
The observation of diverse conformational arrangements is consistent with the 'plasticity' originally ascribed to the complexes in this series.
“This observation is consistent with the surprising “plasticity” originally ascribed to the complexes in this series 54.”
From Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta (2021) · cites this paper as [54]
The collection of models contributing to FFC includes the crystal structure binding mode for the dBET70 ternary complex.
“The crystal structure for the dBET70 ternary complex has been solved 54, and gratifyingly our collection of models contributing to FFC does include this particular binding mode (Figure 2d).”
From Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta (2021) · cites this paper as [54]
Cooperativity plays a role in the efficiency of the VHL-BRD4 degrader MZ1, but is dispensable for CRBN-BRD4 degraders.
“Cooperativity plays a role in the efficiency of the VHL–BRD4 degrader MZ1 (ref.129), but is dispensable for CRBN–BRD4 degraders130.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [130]
Structural studies on VHL and CRBN show that these Cullin-RING E3 ligases form large, modular, U-shaped complexes in which adaptor proteins mediate the interaction between the substrate-binding element and Cullin scaffolds that bind the RING-domain protein RBX1, leading to recruitment of a ubiquitin-conjugated E2.
“Structural studies on VHL and CRBN show that these CullinRING E3 ligases (CRLs) form large, modular, U-shaped complexes in which adaptor proteins mediate the interaction between the substrate-binding element (VHL or CRBN) and Cullin scaffolds that bind the RING-domain protein RBX1, leading to the recruitment of a ubiquitinconjugated E2 (refs 9,46,47,48,49,50,51,52 )”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [46]
Attempts to predict protein interfaces via docking simulations have been reported, but the discovery of PROTACs remains empirical at this time.
“Attempts to predict protein interfaces via docking simulations were recently reported 46,53 , but the discovery of PROTACs remains empirical at this time.”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [46]
Structures of the ternary complex between CRBN, the first bromodomain of BRD4 and diverse PROTACs reveal the plasticity of the interaction, in which different linkers can lead to distinct, target-specific arrangements of the ligase-target interface.
“The structures of the ternary complex between CRBN, the first bromodomain of the target protein bromodomain-containing protein 4 (BRD4) and diverse PROTACs reveal the plasticity of the interaction, in which different linkers can lead to distinct, target-specific arrangements of the ligase-target interface 46 (Fig. 2c).”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [46]
CRBN is one of the most characterized E3 ligases for PROTAC discovery, and a crystal structure of CRBN was solved in complex with a PROTAC and the non-native substrate BRD4, where the compound and target protein bind the atypical CULT and Lon domains of the ligase, respectively.
“The DCAF protein CRBN, which does not feature a WDR domain, is one of the most characterized E3 ligases for PROTAC discovery, and a crystal structure of CRBN was solved in complex with a PROTAC and the non-native substrate BRD4, where the compound and target protein bind the atypical CULT and Lon domains of the ligase, respectively 46 .”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [46]
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- Authors
- Nowak, R. P., DeAngelo, S. L., Buckley, D., He, Z., Donovan, K. A., An, J., Safaee, N., Jedrychowski, M. P., Ponthier, C. M., Ishoey, M., Zhang, T., Mancias, J. D., Gray, N. S., Bradner, J. E., & Fischer, E. S.
- Affiliations
- Harvard University (US)
- Dana-Farber Cancer Institute (US)
- Corresponding author
- Fischer, Eric S.
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2018-06-11
- Volume
- 14
- Issue
- 7
- Pages
- 706-714
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC6202246
- OpenAlex
- W2806672448
- Cited by
- 615
- References
- 51
- Citations by year
- 2026: 66 · 2025: 95 · 2024: 94 · 2023: 62 · 2022: 99 · 2021: 72 · 2020: 61 · 2019: 55 · 2018: 10
- FWCI
- 18.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Friedrich Miescher Institute for Biomedical Research
- National Institutes of Health
- National Cancer Institute (R01CA214608)
- National Institute of General Medical Sciences (P41GM103403)
- National Center for Research Resources (S10RR029205)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- heterobifunctional degraders, binding conformation, protein dimerization, protein-protein docking, ligand selectivity, ubiquitination, cereblon, BRD4
- MeSH terms
- Acetamides, Bromodomain Containing Proteins, Binding Sites, Dose-Response Relationship, Drug, Humans, Ligands, Models, Molecular, Molecular Conformation, Nuclear Proteins, Peptide Hydrolases, Thalidomide, Thiophenes, Transcription Factors, Crystallography, X-Ray, Cell Cycle Proteins, Ubiquitin-Protein Ligases, Adaptor Proteins, Signal Transducing
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