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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The cooperativity of a bifunctional proximity inducer system is attributable to the ligand-induced protein-protein interface.
“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 previous studies of bifunctional proximity inducers, a cooperativity term α has been used to characterize the effects of protein-protein interaction in ternary complex formation.
“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]
When plotted on a logarithmic scale, the MG dose-response curve has a sigmoid shape, in contrast to the bell-shaped dose-response curve produced by bifunctional proximity inducers.
“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]
Several mechanisms contribute to increased selectivity of PROTACs, including steric incapability of some targets to form a productive ternary complex, or lack of a suitably positioned lysine residue for ubiquitination.
“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]
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 Gadd et al., 2017
An essential step in targeted protein degradation is the drug-induced formation of a ternary complex.
“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]
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 [52]
Many effective PROTACs exhibit cooperativity in assembling the components of the ternary complex, implying the presence of adventitious favorable interactions between the target protein and the E3 ligase in the ternary complex.
“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]
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 [129]
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Unexplored therapeutic opportunities in the human genome
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SPR-measured dissociation kinetics of PROTAC ternary complexes influence target degradation rate
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Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development
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Degradation of proteins by PROTACs and other strategies
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Self-citationChemistries of bifunctional PROTAC degraders
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Homolog-Selective Degradation as a Strategy to Probe the Function of CDK6 in AML
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<i>In Silico</i> Modeling of PROTAC-Mediated Ternary Complexes: Validation and Application
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Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity,
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Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies
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Bifunctional chemical probes inducing protein–protein interactions
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Development of selective small molecule MDM2 degraders based on nutlin
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- 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 · 2014: 1
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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