Unveiling the hidden interactome of CRBN molecular glues

Induced proximity by molecular glues refers to strategies that leverage the recruitment of proteins to facilitate their modification, regulation or degradation. As prospective design of molecular glues remains challenging, unbiased discovery methods are necessary to discover new chemical targets. He...

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Bibliographic Details
Published in:Nature communications Vol. 16; no. 1; pp. 6831 - 18
Main Authors: Baek, Kheewoong, Metivier, Rebecca J., Roy Burman, Shourya S., Bushman, Jonathan W., Yoon, Hojong, Lumpkin, Ryan J., Ryan, Julia K., Abeja, Dinah M., Lakshminarayan, Megha, Yue, Hong, Ojeda, Samuel, Xiong, Yuan, Che, Jianwei, Verano, Alyssa L., Schmoker, Anna M., Gray, Nathanael S., Donovan, Katherine A., Fischer, Eric S.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 24.07.2025
Nature Publishing Group
Nature Portfolio
Subjects:
101/28
13
13/1
13/106
49/56
631/45/475/2290
631/92/507
82/16
82/47
82/58
82/80
82/83
Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - metabolism
Adhesives
Biochemistry
Computer applications
Degradation
Glues
HEK293 Cells
Humanities and Social Sciences
Humans
Identification
Kinases
Lead compounds
Lysates
multidisciplinary
Peptide mapping
Protein Binding
Protein interaction
Proteins
Proteomics
Proteomics - methods
Science
Science (multidisciplinary)
Ubiquitin-protein ligase
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
Workflow
Zinc finger proteins
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Description
Summary:Induced proximity by molecular glues refers to strategies that leverage the recruitment of proteins to facilitate their modification, regulation or degradation. As prospective design of molecular glues remains challenging, unbiased discovery methods are necessary to discover new chemical targets. Here we establish a high throughput affinity proteomics workflow leveraging E3 ligase activity-impaired CRBN-DDB1ΔB in cell lysates for the unbiased identification of molecular glue targets. By mapping the interaction landscape of CRBN-binding molecular glues, we unveil 298 protein targets and demonstrate the utility of enrichment methods for identifying targets overlooked by established methods. We use a computational workflow to estimate target confidence and perform biochemical and structural validation of uncharacterized neo-substrates. We further identify a lead compound for the previously untargeted non-zinc finger PPIL4 through a biochemical screen. Our study provides a comprehensive inventory of targets chemically recruited to CRBN and delivers a robust and scalable workflow for identifying drug-induced protein interactions in cell lysates. Induced proximity by molecular glues is a strategy that leverages the recruitment of proteins to facilitate their modification or degradation. Here the authors present unbiased quantitative proteomic, biochemical and computational workflows that uncover hundreds of CRBN molecular glue targets using recombinant protein and cell lysate.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-025-62099-w