ArticleNature structural & molecular biology2025
Chimeric deubiquitinase engineering reveals structural basis for specific inhibition of the mitophagy regulator USP30.
Article in Nature structural & molecular biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Mitochondrial quality control in health and disease: Updates 2026.Chinese medical journal · 2026Review
- Mechanisms and Therapeutic Potential of Targeting Mitophagy in Neurodegenerative Diseases.Molecular neurobiology · 2026Review
- Global analysis of cancer cell responses to USP9X inhibition.The EMBO journal · 2026Article
- Protein structural dynamics in covalent drug design: insights from irreversible and reversible covalent inhibitors.RSC chemical biology · 2026Review
- Function and regulation of the mitochondrial stress response.Nature structural & molecular biology · 2026Review
- Mitochondrial pearling: membrane biophysics, CaFrontiers in cell and developmental biology · 2026Review
- Targeting mitochondria for the treatment of neurodegenerative diseases.Frontiers in neuroscience · 2026Review
- Modulation of mitochondrial quality control in sepsis by traditional Chinese medicine: mechanistic insights and translational perspectives.Frontiers in pharmacology · 2026Review
- Review
- Use of a High-Affinity Ubiquitin-Binding Domain to Detect and Purify Ubiquitinated Substrates and Their Interacting Proteins.Bio-protocol · 2025Article
- A structural switch reveals how to disarm USP30 and unlock mitophagy.Nature structural & molecular biology · 2025Article
- Structural Dynamics of the Ubiquitin Specific Protease USP30 in Complex with a Cyanopyrrolidine-Containing Covalent Inhibitor.Journal of proteome research · 2025Article
- Spotlight on USP30: structure, function, disease and target inhibition.Frontiers in pharmacology · 2025Review
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Authors and funding
5 authors.
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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.
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