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TitleCo-opting the E3 ligase KLHDC2 for targeted protein degradation by small molecules.
Journal, issue, pagesNat Struct Mol Biol, Vol. 31, Issue 2, Page 311-322, Year 2024
Publish dateJan 4, 2024
AuthorsChristopher M Hickey / Katherine M Digianantonio / Kurt Zimmermann / Alicia Harbin / Connor Quinn / Avani Patel / Peter Gareiss / Amanda Chapman / Bernadette Tiberi / Jennifer Dobrodziej / John Corradi / Angela M Cacace / David R Langley / Miklós Békés /
PubMed AbstractTargeted protein degradation (TPD) by PROTAC (proteolysis-targeting chimera) and molecular glue small molecules is an emerging therapeutic strategy. To expand the roster of E3 ligases that can be ...Targeted protein degradation (TPD) by PROTAC (proteolysis-targeting chimera) and molecular glue small molecules is an emerging therapeutic strategy. To expand the roster of E3 ligases that can be utilized for TPD, we describe the discovery and biochemical characterization of small-molecule ligands targeting the E3 ligase KLHDC2. Furthermore, we functionalize these KLHDC2-targeting ligands into KLHDC2-based BET-family and AR PROTAC degraders and demonstrate KLHDC2-dependent target-protein degradation. Additionally, we offer insight into the assembly of the KLHDC2 E3 ligase complex. Using biochemical binding studies, X-ray crystallography and cryo-EM, we show that the KLHDC2 E3 ligase assembles into a dynamic tetramer held together via its own C terminus, and that this assembly can be modulated by substrate and ligand engagement.
External linksNat Struct Mol Biol / PubMed:38177675
MethodsEM (single particle) / X-ray diffraction
Resolution1.418 - 3.74 Å
Structure data

40477

8sh2

EMDB-40477, PDB-8sh2:
KLHDC2 in complex with EloB and EloC
Method: EM (single particle) / Resolution: 3.74 Å

PDB-8sge:
KLHDC2 Kelch Domain with ligand KDRLKZ-1
Method: X-RAY DIFFRACTION / Resolution: 1.509 Å

PDB-8sgf:
KLHDC2 Kelch Domain with KLHDC2 c-terminal peptide bound
Method: X-RAY DIFFRACTION / Resolution: 1.418 Å

Chemicals

ChemComp-GOL:
GLYCEROL / Glycerol

ChemComp-ZWS:
[(5P)-5-{3-[(2R)-butan-2-yl]-7-[(2-methoxyethoxy)carbonyl]-2-oxo-5,6,7,8-tetrahydro-1,7-naphthyridin-1(2H)-yl}-2-oxopyridin-1(2H)-yl]acetic acid

ChemComp-HOH:
WATER / Water

Source
  • homo sapiens (human)
KeywordsPEPTIDE BINDING PROTEIN / KLHDC2

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