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TitleStructural basis for DCAF2 as a novel E3 ligase for PROTAC-mediated targeted protein degradation.
Journal, issue, pagesStructure, Vol. 33, Issue 12, Page 2020-22028.e7, Year 2025
Publish dateDec 4, 2025
AuthorsEvan J McMahon / Alexander G Cioffi / Patrick R Visperas / Yueqing Lin / Michael Shaghafi / Courtney M Daczkowski / Johannes C Hermann / Robert A Everley / Richard M Neve / Daniel A Erlanson / Kevin R Webster / Vikram Narayan / Weiru Wang /
PubMed AbstractTargeted protein degradation (TPD) leverages the ubiquitin-proteasome system to eliminate disease-causing proteins via E3 ligases. To date, the field is limited to utilizing a few of the over 600 ...Targeted protein degradation (TPD) leverages the ubiquitin-proteasome system to eliminate disease-causing proteins via E3 ligases. To date, the field is limited to utilizing a few of the over 600 human E3 ligases. To expand this repertoire, we conducted structural and functional validation of DDB1 (Damage-specific DNA binding protein 1) and Cullin-associated factor (DCAF)2 (DTL/CDT2), a Cullin4-RING ligase substrate adaptor implicated in DNA damage response and cancer, as a novel E3 for TPD. Cryoelectron microscopy (cryo-EM) structures of the DCAF2:DDB1:DDA1 complex (3.3 Å), a ligand bound complex (3.1 Å), and a ternary complex with a covalent proteolysis-targeting chimera (PROTAC) and BRD4 (3.4 Å) reveal PROTAC-mediated substrate recruitment. Using covalent bifunctional tool compounds engaging residue C141 in the WD40 domain, we demonstrate robust ubiquitination in biochemical assays and cellular TPD using the COFFEE (covalent functionalization followed by E3 electroporation) method. These findings position DCAF2 as a promising E3 adaptor for PROTAC strategies and identify C141 as a relevant site for future PROTAC discovery.
External linksStructure / PubMed:41045927
MethodsEM (single particle)
Resolution3.05 - 3.36 Å
Structure data

45224

9c5t

EMDB-45224, PDB-9c5t:
Cryo EM structure of DCAF2
Method: EM (single particle) / Resolution: 3.36 Å

45225

9c5u

EMDB-45225, PDB-9c5u:
Cryo EM structure of DCAF2:Compound 1 complex
Method: EM (single particle) / Resolution: 3.05 Å

45226

9c5v

EMDB-45226, PDB-9c5v:
Cryo EM structure of a DCAF2:degrader:BRD4 ternary complex
Method: EM (single particle) / Resolution: 3.36 Å

Chemicals

PDB-1aum:
HIV CAPSID C-TERMINAL DOMAIN (CAC146)

PDB-1auo:
CARBOXYLESTERASE FROM PSEUDOMONAS FLUORESCENS

Source
  • homo sapiens (human)
KeywordsLIGASE / DCAF2 / E3 ligase / DTL / DDB1 / covalent / fragment / DDA1 / BRD4 / degrader

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