9F6G

Human USP30 chimera bound to Ubiquitin-PA

9F6G の概要

• エントリーDOI: 10.2210/pdb9f6g/pdb
• 関連するPDBエントリー: 9F19
• 分子名称: Ubiquitin carboxyl-terminal hydrolase 30,Ubiquitin carboxyl-terminal hydrolase 14,Ubiquitin carboxyl-terminal hydrolase 35, Polyubiquitin-B, prop-2-en-1-amine, ... (4 entities in total)
• 機能のキーワード: usp30, ubiquitin, dub, deubiquitinating enzyme, usp14, usp35, mitophagy, usp, ubiquitin-specific protease, ubiquitin carboxyl-terminal hydrolase 30, ubiquitin-pa, ub-pa, hydrolase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 44703.54

構造登録者

Kazi, N.H.,Gersch, M. (登録日: 2024-05-01, 公開日: 2025-03-19, 最終更新日: 2025-05-14)

主引用文献

Kazi, N.H.,Klink, N.,Gallant, K.,Kipka, G.M.,Gersch, M.
Chimeric deubiquitinase engineering reveals structural basis for specific inhibition of the mitophagy regulator USP30.
Nat.Struct.Mol.Biol., 2025

PubMed Abstract: The mitochondrial deubiquitinase ubiquitin-specific protease (USP) 30 negatively regulates PINK1-parkin-driven mitophagy. Whether enhanced mitochondrial quality control through inhibition of USP30 can protect dopaminergic neurons is currently being explored in a clinical trial for Parkinson's disease. However, the molecular basis for specific inhibition of USP30 by small molecules has remained elusive. Here we report the crystal structure of human USP30 in complex with a specific inhibitor, enabled by chimeric protein engineering. Our study uncovers how the inhibitor extends into a cryptic pocket facilitated by a compound-induced conformation of the USP30 switching loop. Our work underscores the potential of exploring induced pockets and conformational dynamics to obtain deubiquitinase inhibitors and identifies residues facilitating specific inhibition of USP30. More broadly, we delineate a conceptual framework for specific USP deubiquitinase inhibition based on a common ligandability hotspot in the Leu73 ubiquitin binding site and on diverse compound extensions. Collectively, our work establishes a generalizable chimeric protein-engineering strategy to aid deubiquitinase crystallization and enables structure-based drug design with relevance to neurodegeneration.

PubMed: 40325251
DOI: 10.1038/s41594-025-01534-4

実験手法

X-RAY DIFFRACTION (1.5 Å)