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Structural basis of PROTAC cooperative recognition for selective protein degradation
Open accessAbstract
Inducing macromolecular interactions with small molecules to activate cellular signaling is a challenging goal. PROTACs (proteolysis-targeting chimeras) are bifunctional molecules that recruit a target protein in proximity to an E3 ubiquitin ligase to trigger protein degradation. Structural elucidation of the key ternary ligase-PROTAC-target species and its impact on target degradation selectivity remain elusive. We solved the crystal structure of Brd4 degrader MZ1 in complex with human VHL and the Brd4 bromodomain (Brd4 BD2). The ligand folds into itself to allow formation of specific intermolecular interactions in the ternary complex. Isothermal titration calorimetry studies, supported by surface mutagenesis and proximity assays, are consistent with pronounced cooperative formation of ternary complexes with Brd4 BD2. Structure-based-designed compound AT1 exhibits highly selective depletion of Brd4 in cells. Our results elucidate how PROTAC-induced de novo contacts dictate preferential recruitment of a target protein into a stable and cooperative complex with an E3 ligase for selective degradation.
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In the citing paper
“By contrast, the cooperativity of a bifunctional proximity inducer system is attributable to the ligand-induced protein–protein interface37.”
From Defining molecular glues with a dual-nanobody cannabidiol sensor (2022) · cites this paper as [37]
In the citing paper
“In previous studies of bifunctional proximity inducers, a cooperativity term (represented by α) has been used to characterize the effects of protein–protein interaction in ternary complex formation36,37.”
From Defining molecular glues with a dual-nanobody cannabidiol sensor (2022) · cites this paper as [37]
In the citing paper
“When plotted on a logarithmic scale, the MG dose-response curve has a familiar sigmoid shape (Fig. 7c), which is in stark contrast to the bell-shaped dose-response curve produced by the bifunctional proximity inducers36,37.”
From Defining molecular glues with a dual-nanobody cannabidiol sensor (2022) · cites this paper as [37]
In the citing paper
“Several mechanisms have been shown to contribute to this increase in selectivity. This includes steric incapability of some targets to form a productive ternary complex, or lack of a suitably positioned lysine residue for ubiquitination.62−69”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [63]
In the citing paper
“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 Gadd et al., 2017
In the citing paper
“An essential step in targeted protein degradation is the drug-induced formation of a ternary complex10,43.”
From Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders (2023) · cites this paper as [10]
In the citing paper
“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 [52]
In the citing paper
“The observation that many effective PROTACs exhibit cooperativity in assembling the components of the ternary complex 35, 52, 53 implies the presence of adventitious favorable interactions between the target protein and the E3 ligase in the ternary complex.”
From Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta (2021) · cites this paper as [52]
In the citing paper
“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 [129]
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Self-citationBromodomain and extraterminal (BET) proteins: biological functions, diseases and targeted therapy
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Hughes, S. J., & Ciulli, A. (2017) · Essays in Biochemistry · doi:10.1042/ebc20170041 · Cited by 240
Self-citationA selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo
Kofink, C. C., Trainor, N. B., Mair, B., Wöhrle, S., Wurm, M., Mischerikow, N., Roy, M. J., Bader, G., Greb, P., Garavel, G., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-33430-6 · Cited by 239
Self-citationExtended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2
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Recent Developments in PROTAC‐Mediated Protein Degradation: From Bench to Clinic
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E3 Ligase Ligands in Successful PROTACs: An Overview of Syntheses and Linker Attachment Points
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Proteolysis Targeting Chimeras (PROTACs) of Anaplastic Lymphoma Kinase (ALK)
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Han, X., Zhao, L., Xiang, W., Qin, C., Miao, B., Xu, T., Wang, M., Yang, C., Chinnaswamy, K., Stuckey, J. A., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01393 · Cited by 225
PRosettaC: Rosetta Based Modeling of PROTAC Mediated Ternary Complexes
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Self-citationFunctional TRIM24 degrader via conjugation of ineffectual bromodomain and VHL ligands
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Targeted protein degradation via intramolecular bivalent glues
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Self-citationGuo, W., Qi, X., Yu, X., Liu, Y., Chung, C.-I., Bai, F., Lin, X., Lu, D., Wang, L., Chen, J., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-17997-6 · Cited by 228
PROTAC-DB: an online database of PROTACs
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Medicinal chemistry strategies for discovering antivirals effective against drug-resistant viruses
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Efficient targeted degradation via reversible and irreversible covalent PROTACs
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Application of Fragment-Based Drug Discovery to Versatile Targets
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Proximity-Based Modalities for Biology and Medicine
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Self-citationPrey for the Proteasome: Targeted Protein Degradation—A Medicinal Chemist's Perspective
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Self-citationChasing molecular glue degraders: screening approaches
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Unifying principles of bifunctional, proximity-inducing small molecules
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In Silico Modeling of PROTAC-Mediated Ternary Complexes: Validation and Application
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Targeting cancer with small-molecule pan-KRAS degraders
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Self-citation
Metadata
- Authors
- Gadd, M. S., Testa, A., Lucas, X., Chan, K.-H., Chen, W., Lamont, D. J., Zengerle, M., & Ciulli, A.
- Affiliations
- University of Dundee (GB)
- Corresponding author
- Ciulli, Alessio
- Venue
- Nature Chemical Biology
- Published
- 2017-03-13
- Volume
- 13
- Issue
- 5
- Pages
- 514-521
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC5392356
- OpenAlex
- W2597078857
- Cited by
- 1,242
- References
- 60
- Citations by year
- 2026: 173 · 2025: 173 · 2024: 176 · 2023: 159 · 2022: 138 · 2021: 129 · 2020: 133 · 2019: 86 · 2018: 46 · 2017: 26
- FWCI
- 33.34
- 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)
- Lancaster EPrints (Lancaster University) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion, other-oa)
- Funders
- Wellcome Trust (100476, 094090/Z/10/Z, 094090, 100476/Z/12/Z)
- Diamond Light Source (MX10071)
- European Commission (H2020-MSCA-IF-2014, H2020- MSCA-IF-2015, H2020, 655516, H2020‐MSCA‐IF, H2020-MSCA)
- Directorate for Biological Sciences
- Horizon 2020 Framework Programme (H2020‐MSCAIF‐2014, H2020-MSCA, MSCA-IF-2014, H2020-MSCA-IF-2015)
- Medical Research Council
- Biotechnology and Biological Sciences Research Council (BB/J001201/1, BB/J001201/2)
- H2020 Marie Skłodowska-Curie Actions (H2020-MSCA-IF-2014, H2020-MSCA-IF-2014-655516, H2020, 655516, H2020-MSCA-IF, H2020-MSCA-IF-2015, H2020-MSCA, 806323, H2020-MSCA-IF-2015-806323)
- FP7 Ideas: European Research Council (311460)
- 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 › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Keywords
- PROTACs, BRD4, VHL E3 ubiquitin ligase, bromodomain, selective protein degradation, crystal structure, ternary complex, structure-based drug design, ubiquitination
- MeSH terms
- Elongin, Bromodomain Containing Proteins, Amino Acid Sequence, Dipeptides, Heterocyclic Compounds, 3-Ring, Humans, Models, Molecular, Nuclear Proteins, Protein Binding, Protein Conformation, Structure-Activity Relationship, Thermodynamics, Transcription Factors, Crystallography, X-Ray, Cell Cycle Proteins, Ubiquitin-Protein Ligases, Multiprotein Complexes, Von Hippel-Lindau Tumor Suppressor Protein, Small Molecule Libraries, Proteolysis
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