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Structural assembly of cullin-RING ubiquitin ligase complexes
Open accessAbstract
The cullin-RING ubiquitin ligases (CRLs) are the largest family of multi-subunit E3 ligases in eukaryotes, which ubiquitinate protein substrates in numerous cellular pathways. CRLs share a common arched scaffold and a RING domain catalytic subunit, but use different adaptors and substrate receptors to assemble unique E3 machineries. In comparison to the first CRL structure, recent findings have revealed increased complexity in the overall architecture and assembly mode of CRLs, including multi-domain organization, inter-domain flexibility, and subunit dimerization. These features highlight the capacity of CRLs to catalyze protein ubiquitination under distinct cellular contexts and in response to diverse signals. As the first installment of a two-review series, this article will focus on recent advances in our understanding of CRL assembly mechanisms.
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“Structural studies show that cul4 can rotate up to 150° around DDB1, the cRBN adaptor, generating a large ubiquitylation zone spacious enough to allow cRBN autoubiquitylation without a substrate being present (Zimmerman et al. 2010;Fischer et al. 2014).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Zimmerman et al. 2010
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“cDK12 therefore acts as a pseudo-substrate receptor which positions cycK within the expansive ubiquitylation zone of cRl4 ligases (Zimmerman et al. 2010;Słabicki et al. 2020a).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Zimmerman et al. 2010
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“ubiquitin E3 ligases serve as scaffolds between a target protein and an activated ubiquitin E2 conjugating enzyme charged with a ubiquitin molecule (E2–Ub), by binding both molecules, then catalysing the transfer of ubiquitin from the active site cysteine of the E2 onto a lysine side chain of a target protein104–107.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [104]
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Metadata
- Authors
- Zimmerman, E. S., Schulman, B. A., & Zheng, N.
- Affiliations
- University of Washington (US)
- St. Jude Children's Research Hospital (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Zheng, Ning
- Venue
- Current Opinion in Structural Biology
- Publisher
- Elsevier BV
- Published
- 2010-12
- Volume
- 20
- Issue
- 6
- Pages
- 714-721
- ISSN
- 0959-440X (ISSN-L)
- PMC
- PMC3070871
- OpenAlex
- W2029890158
- Cited by
- 227
- References
- 62
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 12 · 2023: 11 · 2022: 14 · 2021: 14 · 2020: 15 · 2019: 18 · 2018: 13 · 2017: 12 · 2016: 17 · 2015: 18 · 2014: 14 · 2013: 21 · 2012: 17
- FWCI
- 1.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Current Opinion in Structural Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (R01CA107134)
- National Institute of General Medical Sciences (F32GM093497, R01GM069530)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- cullin-RING ubiquitin ligases, E3 ubiquitin ligase, ubiquitination, RING domain, adaptor proteins, substrate receptor, subunit dimerization
- MeSH terms
- Animals, Humans, Protein Structure, Secondary, Protein Structure, Quaternary, Ubiquitin-Protein Ligases, F-Box Proteins, Protein Multimerization
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