Discovery of small-molecule positive allosteric modulators of Parkin E3 ligase.
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ABSTRACT: Pharmacological activation of the E3 ligase Parkin represents a rational therapeutic intervention for the treatment of Parkinson's disease. Here we identify several compounds that enhance the activity of wildtype Parkin in the presence of phospho-ubiquitin and act as positive allosteric modulators (PAMs). While these compounds activate Parkin in a series of biochemical assays, they do not act by thermally destabilizing Parkin and fail to enhance the Parkin translocation rate to mitochondria or to enact mitophagy in cell-based assays. We conclude that in the context of the cellular milieu the therapeutic window to pharmacologically activate Parkin is very narrow.
SUBMITTER: Shlevkov E
PROVIDER: S-EPMC8733272 | biostudies-literature |
REPOSITORIES: biostudies-literature
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