Co-opting the E3 Ligase KLHDC2 for Targeted Protein Degradation by Small Molecules

Overview

Journal Nat Struct Mol Biol

Specialties Cell Biology
Molecular Biology

Date 2024 Jan 4

PMID 38177675

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

Miklos Bekes

Affiliations

Soon will be listed here.

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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