- PDB-8sge: KLHDC2 Kelch Domain with ligand KDRLKZ-1 -
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Basic information
Entry
Database: PDB / ID: 8sge
Title
KLHDC2 Kelch Domain with ligand KDRLKZ-1
Components
Kelch domain-containing protein 2
Keywords
PEPTIDE BINDING PROTEIN / KLHDC2
Function / homology
Function and homology information
ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / Cul2-RING ubiquitin ligase complex / ubiquitin-like ligase-substrate adaptor activity / nuclear membrane / proteasome-mediated ubiquitin-dependent protein catabolic process / nuclear body / protein ubiquitination / nucleoplasm / nucleus Similarity search - Function
Journal: Nat Struct Mol Biol / Year: 2024 Title: Co-opting the E3 ligase KLHDC2 for targeted protein degradation by small molecules. Authors: Christopher M Hickey / Katherine M Digianantonio / Kurt Zimmermann / Alicia Harbin / Connor Quinn / Avani Patel / Peter Gareiss / Amanda Chapman / Bernadette Tiberi / Jennifer Dobrodziej / ...Authors: Christopher 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 / Abstract: 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 ...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.
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