Discovery and structural characterization of a VHL-mediated molecular glue degrader targeting cysteine dioxygenase
Open accessAbstract
VHL is one of the most widely exploited E3 ligases to induce ubiquitination and subsequent targeted protein degradation. Although many VHL-mediated bifunctional proteolysis-targeting chimeras (PROTACs) are known in the literature, bona fide example of small molecule glue degrader that recruit client protein to interact with VHL remains scant. Here, we report a small molecular glue degrader discovered from protein microarrays. Using several biochemical, biophysical and cellular assays, we demonstrate these compounds induce neo-interactions between VHL and cysteine dioxygenase (CDO1), leading to the polyubiquitination and degradation of CDO1. Structural characterization of this VHL/CDO1/glue ternary complex maps the degron to a composite surface formed by multiple discontiguous regions of hCDO1. Collectively, our studies reveal the mechanism of action of a novel small molecular glue degrader that directly recruits CDO1 to VHL, presenting a new avenue for targeted protein degradation.
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X-ray structures of the ternary complex confirmed the MG mode of action.
“X-ray structures of the ternary complex confirmed the MG mode of action.160”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [160]
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Chasing molecular glue degraders: screening approaches
Domostegui, A., Nieto-Barrado, L., Perez-Lopez, C., & Mayor-Ruiz, C. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00197g · Cited by 200 · see citing works
Design principles for cyclin K molecular glue degraders
Kozicka, Z., Suchyta, D. J., Focht, V., Kempf, G., Petzold, G., Jentzsch, M., Zou, C., Di Genua, C., Donovan, K. A., Coomar, S., et al. (2024) · Nature Chemical Biology · doi:10.1038/s41589-023-01409-z · Cited by 113 · see citing works
“1f–h, 7 – 15 ).”
- Authors
- Ma, X.
- Affiliations
- Novartis (Switzerland) (CH)
- Corresponding author
- Ma, Xiaolei
- ORCID
- Ma, Xiaolei
- Venue
- Acta Crystallographica Section A Foundations and Advances
- Published
- 2021-07-30
- Volume
- 77
- Issue
- a1
- Pages
- a245-a245
- ISSN
- 2053-2733 (ISSN-L)
- OpenAlex
- W3211005818
- Cited by
- 2
- References
- 0
- Citations by year
- 2023: 1 · 2022: 1
- FWCI
- 0.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Acta Crystallographica Section A Foundations and Advances (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
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- VHL, cysteine dioxygenase, CDO1, molecular glues, PROTACs, targeted protein degradation, E3 ubiquitin ligase, polyubiquitination, ternary complex structure, degron, protein microarrays, protein-protein interaction
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