2025-05-05 マックス・プランク研究所
Inhibition of the deubiquitinase USP30 promotes mitophagy and thus mitochondrial renewal in dopaminergic nerve cells and could therefore form the basis for an innovative therapy for Parkinson’s disease.
<関連情報>
- https://www.mpg.de/24658988/promising-parkinson-s-drug-decoded
- https://www.nature.com/articles/s41594-025-01534-4
キメラデユビキチナーゼ工学によるマイトファジー制御因子USP30の特異的阻害の構造基盤の解明 Chimeric deubiquitinase engineering reveals structural basis for specific inhibition of the mitophagy regulator USP30
Nafizul Haque Kazi,Nikolas Klink,Kai Gallant,Gian-Marvin Kipka & Malte Gersch
Nature Structural & Molecular Biology Published:05 May 2025
DOI:https://doi.org/10.1038/s41594-025-01534-4
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.
