Modeling the CRL4A ligase complex to predict target protein ubiquitination induced by cereblon-recruiting PROTACs
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PROteolysis TArgeting Chimeras (PROTACs) are hetero-bifunctional small molecules that can simultaneously recruit target proteins and E3 ligases to form a ternary complex, promoting target protein ubiquitination and degradation via the Ubiquitin-Proteasome System (UPS). PROTACs have gained increasing attention in recent years due to certain advantages over traditional therapeutic modalities and enabling targeting of previously "undruggable" proteins. To better understand the mechanism of PROTAC-induced Target Protein Degradation (TPD), several computational approaches have recently been developed to study and predict ternary complex formation. However, mounting evidence suggests that ubiquitination can also be a rate-limiting step in PROTAC-induced TPD. Here, we propose a structure-based computational approach to predict target protein ubiquitination induced by cereblon (CRBN)-based PROTACs by leveraging available structural information of the CRL4A ligase complex (CRBN/DDB1/CUL4A/Rbx1/NEDD8/E2/Ub). We generated ternary complex ensembles with Rosetta, modeled multiple CRL4A ligase complex conformations, and predicted ubiquitination efficiency by separating the ternary ensemble into productive and unproductive complexes based on the proximity of the ubiquitin to accessible lysines on the target protein. We validated our CRL4A ligase complex models with published ternary complex structures and additionally employed our modeling workflow to predict ubiquitination efficiencies and sites of a series of cyclin-dependent kinases (CDKs) after treatment with TL12-186, a pan-kinase PROTAC. Our predictions are consistent with CDK ubiquitination and site-directed mutagenesis of specific CDK lysine residues as measured using a NanoBRET ubiquitination assay in HEK293 cells. This work structurally links PROTAC-induced ternary formation and ubiquitination, representing an important step toward prediction of target "degradability."
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Some recent studies have shown that only ternary complex models with optimal target-lysine accessibility for E2 could predict target degradation outcomes.
“Moreover, some recent studies have shown that only the ternary complex models with optimal target-lysine accessibility for the E2 could predict target degradation outcomes.[181][182][183]”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [182]
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Application of Fluorescence- and Bioluminescence-Based Biosensors in Cancer Drug Discovery
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Unveiling the hidden interactome of CRBN molecular glues with chemoproteomicsPreprint
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A comprehensive primer and review of PROTACs and their In Silico design
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G protein-coupled receptor–targeted proteolysis-targeting chimeras in cancer therapeutics
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Molecular Latent Space Simulators for Distributed and Multimolecular Trajectories
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The 17 th EFMC Short Course on Medicinal Chemistry on Small Molecule Protein Degraders
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The rise of targeting chimeras (TACs): next-generation medicines that preempt cellular events
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PROTAC-induced protein structural dynamics in targeted protein degradationPreprint
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Methods to Study the Molecular Mechanism and Drive the Design of Protein Degraders
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Dynamic characteristics of proteolysis-targeting chimera systems revealed by in silico computations
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Molecular glue CELMoD compounds are allosteric regulators of cereblon conformationPreprint
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P4ward: An Automated Modeling Platform for Protac Ternary Complexes
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Computational Modeling of PROTAC Ternary Complexes and Linker Design
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P4ward: an automated modelling platform for Protac ternary complexesPreprint
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PROTAC-induced Protein Structural Dynamics in Targeted Protein DegradationPreprint
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- Authors
- Bai, N., Riching, K. M., Makaju, A., Wu, H., Acker, T. M., Ou, S.-C., Zhang, Y., Shen, X., Bulloch, D. N., Rui, H., Gibson, B. W., Daniels, D. L., Urh, M., Rock, B. M., & Humphreys, S. C.
- Affiliations
- Amgen (United States) (US)
- Promega (United States) (US)
- Corresponding author
- Bai, Nan
- Riching, Kristin M.
- Humphreys, Sara C.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2022-04
- Volume
- 298
- Issue
- 4
- Pages
- 101653
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC9019245
- OpenAlex
- W4210738474
- Cited by
- 77
- References
- 57
- Citations by year
- 2026: 8 · 2025: 20 · 2024: 17 · 2023: 16 · 2022: 16
- FWCI
- 5.71
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Amgen Inc
- 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 › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- PROTACs, cereblon, ternary complex formation, ubiquitin-proteasome system, structure-based prediction, cyclin-dependent kinases, lysine ubiquitination sites, undruggable proteins
- MeSH terms
- Humans, Models, Molecular, Protein Structure, Tertiary, Ubiquitin, Ubiquitin-Protein Ligases, Ubiquitination, HEK293 Cells, Proteolysis
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