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Structure paper

TitleStructural basis of CSN-mediated SCF deneddylation.
Journal, issue, pagesNat Commun, Vol. 17, Issue 1, Page 951, Year 2026
Publish dateJan 23, 2026
AuthorsShan Ding / Julie A Clapperton / Märt-Erik Mäeots / Simone Kunzelmann / Mohammed Shaaban / Radoslav I Enchev /
PubMed AbstractCullin-RING ligases (CRLs) are the largest family of E3 ligases, with ubiquitination activity dynamically regulated by neddylation and deneddylation by the COP9 signalosome (CSN). CSN-mediated ...Cullin-RING ligases (CRLs) are the largest family of E3 ligases, with ubiquitination activity dynamically regulated by neddylation and deneddylation by the COP9 signalosome (CSN). CSN-mediated deneddylation not only deactivates CRLs but also enables substrate receptor exchange. Although CSN is a promising drug target, the structural basis underlying its catalytic mechanism remains unclear. Here, we use cryo-electron microscopy (cryo-EM) to uncover distinct functional states of CSN-CRL (SCF) complexes, capturing key intermediates of the deneddylation cycle. We visualise an autoinhibited docking state and a catalytic intermediate in which CSN5 Ins-1 loop, RBX1 RING and neddylated Cullin WHB domains are repositioned for isopeptide cleavage. We further resolve four dissociation intermediates that define the stepwise release of CSN from its product, with RBX1 RING stabilising key interactions. Additionally, our structures locate CSNAP within a CSN3-CSN8 groove. Together, our study provides a mechanistic model for CSN function and informs the rational design of CSN-targeted therapeutics.
External linksNat Commun / PubMed:41577659 / PubMed Central
MethodsEM (single particle)
Resolution2.95 - 4.0 Å
Structure data

53256

9qo4

EMDB-53256, PDB-9qo4:
Dissociation-state-3 of 9-subunit CSN and SCF (SKP1-SKP2-CKS1) complex
Method: EM (single particle) / Resolution: 2.95 Å

53257

9qo5

EMDB-53257, PDB-9qo5:
Dissociation-state-4 of 9-subunit CSN and SCF (SKP1-SKP2-CKS1) complex
Method: EM (single particle) / Resolution: 4.0 Å

53258

9qo6

EMDB-53258, PDB-9qo6:
9-subunit COP9 signalosome complex
Method: EM (single particle) / Resolution: 3.0 Å

Chemicals

ChemComp-IHP:
INOSITOL HEXAKISPHOSPHATE

ChemComp-ZN:
Unknown entry

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsLIGASE / E3 ligases / COP9 signalosome / HYDROLASE

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