Chimeric deubiquitinase engineering reveals structural basis for specific inhibition of the mitophagy regulator USP30.

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 inh

SUBMITTER: Kazi NH 

PROVIDER: S-EPMC12440824 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature