ArticleNature communications2024
Activation of parkin by a molecular glue.
Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed.
- Cell-Type-Specific Calibration of Mitochondrial Ubiquitination in Stem Cell Fate Decisions.Stem cell reviews and reports · 2026Review
- Review
- Species-dependent activities of the PINK1-parkin axis.Translational neurodegeneration · 2026Review
- Ubiquitination-dependent regulation of ferroptosis in ischemic heart and brain.Redox biology · 2026Review
- Ubiquitin family as novel protein partners for molecular glues.npj drug discovery · 2026Review
- Gaps in the Parkinson's disease therapeutic clinical pipeline: A focus on approaches targeting disease pathobiology.Journal of Parkinson's disease · 2026Review
- Alternative Translation Initiation in PRKN Delays the Onset of Parkinson's Disease and Offers a Therapeutic Target.Annals of neurology · 2026Article
- Mitochondrial homeostasis: the central hub governing the progression of atherosclerosis.Precision clinical medicine · 2026Review
- The role of phospho-ubiquitin in mitochondrial health and diseases.The Journal of biological chemistry · 2026Review
- Phospho-ubiquitin: rewriting the ubiquitin code.Molecular neurodegeneration · 2026Review
- Neural cell state modulation bybioRxiv : the preprint server for biology · 2026Article
- Function and regulation of the mitochondrial stress response.Nature structural & molecular biology · 2026Review
- Degrons and degradation signals beyond short linear motifs.Nature chemical biology · 2026Review
- Mitophagy-driven multidimensional regulation of tumor immune evasion and context-dependent therapeutic strategies.Journal of translational medicine · 2026Review
- APOE4 impairs Nrf2-PINK1/Parkin-dependent mitochondrial clearance through disrupted antioxidant and mitophagy signaling.Free radical biology & medicine · 2026Article
- Novel insight into PINK1/parkin-associated autophagy implicated in Parkinson disease.Translational neuroscience · 2026Review
- Rethinking PINK1/Parkin-mediated mitophagy in Parkinson's disease: functional continuity and activation-clearance uncoupling.Frontiers in aging neuroscience · 2026Review
- Mitophagy and Cellular Homeostasis in Kidney Diseases: Mechanisms and Potential Therapeutics.International journal of biological sciences · 2026Review
- Autophagy and mitophagy at the synapse and beyond: implications for learning, memory and neurological disorders.Autophagy · 2026Review
- Mitophagy in the pathogenesis and management of disease.Cell research · 2026Review
Corrections and comments
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Authors and funding
15 authors.
Funding
Abstract
Mutations in parkin and PINK1 cause early-onset Parkinson's disease (EOPD). The ubiquitin ligase parkin is recruited to damaged mitochondria and activated by PINK1, a kinase that phosphorylates ubiquitin and the ubiquitin-like domain of parkin. Activated phospho-parkin then ubiquitinates mitochondrial proteins to target the damaged organelle for degradation. Here, we present the mechanism of activation of a new class of small molecule allosteric modulators that enhance parkin activity. The compounds act as molecular glues to enhance the ability of phospho-ubiquitin (pUb) to activate parkin. Ubiquitination assays and isothermal titration calorimetry with the most active compound (BIO-2007817) identify the mechanism of action. We present the crystal structure of a closely related compound (BIO-1975900) bound to a complex of parkin and two pUb molecules. The compound binds next to pUb on RING0 and contacts both proteins. Hydrogen-deuterium exchange mass spectrometry (HDX-MS) experiments confirm that activation occurs through release of the catalytic Rcat domain. In organello and mitophagy assays demonstrate that BIO-2007817 partially rescues the activity of parkin EOPD mutants, R42P and V56E, offering a basis for the design of activators as therapeutics for Parkinson's disease.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.