ArticleNature structural & molecular biology2024
Co-opting the E3 ligase KLHDC2 for targeted protein degradation by small molecules.
Article in Nature structural & molecular biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 55 citations in OpenAlex.
- Charged molecular glue discovery enabled by targeted degron display.Nature chemical biology · 2026Article
- Engineering Antibodies into Targeted Chimeras: From Recognition Modules to Programmable Degraders.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- De Novo-Designed Bifunctional Proteins for Targeted Protein Degradation.Journal of the American Chemical Society · 2026Article
- Methods to Study the Molecular Mechanism and Drive the Design of Protein Degraders.Chemical reviews · 2026Review
- Structures of ZYG11B-EloB-EloC-substrate complex reveal mechanisms of CRL2Nature communications · 2026Article
- Overcoming Ligand Discovery Challenges: Developing Peptide-Based Tracers for SPSB2.ACS chemical biology · 2026Article
- KLHDC3 deficiency in mice reveals essential roles in development, survival, and adiposity via the DesCEND ubiquitin pathway.BMC genomics · 2026Article
- Clues for glues: from serendipity to nature's blueprints in degrader discovery.Essays in biochemistry · 2025Review
- Recent advances in targeting protein degradation for tumor immunotherapy.Journal of hematology & oncology · 2025Review
- Degrons: defining the rules of protein degradation.Nature reviews. Molecular cell biology · 2025Review
- Mode of action of a DCAF16-recruiting targeted glue that can selectively degrade BRD9.Nature communications · 2025Article
- Targeted protein degradation for cancer therapy.Nature reviews. Cancer · 2025Review
- Article
- Recommended Tool Compounds: Thienotriazolodiazepines-Derivatized Chemical Probes to Target BET Bromodomains.ACS pharmacology & translational science · 2025Review
- Characteristics of the Kelch domain containing (KLHDC) subfamily and relationships with diseases.FEBS letters · 2025Review
- Implications of frequent hitter E3 ligases in targeted protein degradation screens.Nature chemical biology · 2025Review
- Clozapine as an E3 Ligand for PROTAC Technology.ACS medicinal chemistry letters · 2025Article
- PROteolysis TArgeting Chimeras (PROTACs) and beyond: targeted degradation as a new path to fight microbial pathogens.FEMS microbiology reviews · 2025Review
- Proteolysis Targeting Chimeras (PROTACs) in Breast Cancer Therapy.ChemMedChem · 2024Review
- Structural basis for C-degron selectivity across KLHDCX family E3 ubiquitin ligases.Nature communications · 2024Article
Corrections and comments
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Authors and funding
14 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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 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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.