8SGE

KLHDC2 Kelch Domain with ligand KDRLKZ-1

8SGE の概要

• エントリーDOI: 10.2210/pdb8sge/pdb
• 分子名称: Kelch domain-containing protein 2, GLYCEROL, [(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, ... (4 entities in total)
• 機能のキーワード: klhdc2, peptide binding protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 84127.67

構造登録者

Digianantonio, K.M.,Bekes, M.,Langley, D.R.,Zimmerman, K. (登録日: 2023-04-12, 公開日: 2024-01-03, 最終更新日: 2024-02-28)

主引用文献

Hickey, C.M.,Digianantonio, K.M.,Zimmermann, K.,Harbin, A.,Quinn, C.,Patel, A.,Gareiss, P.,Chapman, A.,Tiberi, B.,Dobrodziej, J.,Corradi, J.,Cacace, A.M.,Langley, D.R.,Bekes, M.
Co-opting the E3 ligase KLHDC2 for targeted protein degradation by small molecules.
Nat.Struct.Mol.Biol., 31:311-322, 2024

PubMed 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.

PubMed: 38177675
DOI: 10.1038/s41594-023-01146-w

実験手法

X-RAY DIFFRACTION (1.509 Å)