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PreprintCited by 117Protein Degradation and InhibitorsUbiquitin and proteasome pathwaysComputational Drug Discovery Methods

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Mining the CRBN Target Space Redefines Rules for Molecular Glue-induced Neosubstrate Recognition

Petzold, Georg, Gainza, Pablo, Annunziato, Stefano, Lamberto, Ilaria, Trenh, Peter, McAllister, Laura, Demarco, Bradley, Schwander, Laura, Bunker, Richard D., Zlotosch, Mary, SriRamaratnam, Rohitha, Gilberto, Samuel, Langousis, Gerasimos, Donckele, Etienne J., Quan, Chao, Strande, Vaik, Donatis, Gian Marco De, Alabi, Shanique B., Alers, Jessica, Matysik, Michelle, Staehly, Camille, Dubois, Aurélie, Osmont, Arnaud, Garskovas, Mackenzie, Lyon, David, Wiedmer, Lars, Oleinikovas, Vladimiras, Lieberherr, Raphael, Rubin, Nooreen T., Lam, Daniel T., Widlund, Nina Ilic, Ritzén, Andreas, Caceres, Ramon Miguel, Vigil, Dominico, Tsai, Jennifer, Wallace, Owen, Peluso, Marisa, Sadok, Amine, Paterson, Alison M., Zarayskiy, Vladislav, Fasching, Bernhard, Bonenfant, Debora, Warmuth, Markus, Castle, John, Townson, Sharon A.·2024·Science
DOI 10.1101/2024.10.07.616933

Preprint — published as 10.1126/science.adt6736 · Paper page

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Abstract

The CRL4 CRBN ubiquitin ligase is leveraged by molecular glue degraders, small molecules that reprogram ligase specificity to induce degradation of clinically relevant neosubstrate proteins. Known CRBN neosubstrates share a generalizable β-hairpin G-loop recognition motif, yet systematic exploration of the CRBN target landscape is still pending. Through computational mining of the human proteome using structure-based approaches, we predict over 1,400 CRBN-compatible β-hairpin G-loop proteins across diverse target classes, identify novel mechanisms of neosubstrate recognition through structurally differentiated helical motifs and molecular surface mimicry, and validate 22 representative neosubstrates with clinical implications. This work broadens the CRBN target space, redefines rules for neosubstrate recognition and establishes a platform for the elimination of challenging drug targets by repurposing CRL4 CRBN through next-generation molecular glue degraders.

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Metadata

Authors
Petzold, G., Gainza, P., Annunziato, S., Lamberto, I., Trenh, P., McAllister, L., Demarco, B., Schwander, L., Bunker, R. D., Zlotosch, M., SriRamaratnam, R., Gilberto, S., Langousis, G., Donckele, E. J., Quan, C., Strande, V., Donatis, G. M. D., Alabi, S. B., Alers, J., Matysik, M., Staehly, C., Dubois, A., Osmont, A., Garskovas, M., Lyon, D., Wiedmer, L., Oleinikovas, V., Lieberherr, R., Rubin, N. T., Lam, D. T., Widlund, N. I., Ritzén, A., Caceres, R. M., Vigil, D., Tsai, J., Wallace, O., Peluso, M., Sadok, A., Paterson, A. M., Zarayskiy, V., Fasching, B., Bonenfant, D., Warmuth, M., Castle, J., & Townson, S. A.
Affiliations
Boston Foundation (US)
Corresponding author
  • Petzold, Georg
  • Castle, John
  • Townson, Sharon A.
ORCID
Venue
Science
Publisher
openRxiv
Published
2024-10-09
Volume
389
Issue
6755
Pages
eadt6736-eadt6736
ISSN
0036-8075 (ISSN-L)
DOI
10.1101/2024.10.07.616933
OpenAlex
W4411983851
Cited by
117
References
2
Citations by year
2026: 73 · 2025: 43 · 2024: 1
FWCI
34.67
Type
journal article
Language
en
Open access
closed
Licence
www.biorxiv.org/about/FAQ#license (vor)
Locations
  • Science (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
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 › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
Keywords
molecular glues, Vav1, protein degradation
MeSH terms
Humans, Protein Binding, Substrate Specificity, Molecular Mimicry, Amino Acid Motifs, Ubiquitin-Protein Ligases, Adaptor Proteins, Signal Transducing, Data Mining, Drug Repositioning, Proteolysis

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