8W31
Crystal structure of parkin (R0RB):2pUb with activator compound
This is a non-PDB format compatible entry.
Summary for 8W31
| Entry DOI | 10.2210/pdb8w31/pdb |
| Related | 7US1 |
| Descriptor | E3 ubiquitin-protein ligase parkin, Ubiquitin, ZINC ION, ... (6 entities in total) |
| Functional Keywords | e3-ubiquitin ligase, ligase, activator |
| Biological source | Rattus norvegicus (Norway rat) More |
| Total number of polymer chains | 3 |
| Total formula weight | 44580.85 |
| Authors | Sauve, V.,Gehring, K. (deposition date: 2024-02-21, release date: 2024-08-21, Last modification date: 2024-10-09) |
| Primary citation | Sauve, V.,Stefan, E.,Croteau, N.,Goiran, T.,Fakih, R.,Bansal, N.,Hadzipasic, A.,Fang, J.,Murugan, P.,Chen, S.,Fon, E.A.,Hirst, W.D.,Silvian, L.F.,Trempe, J.F.,Gehring, K. Activation of parkin by a molecular glue. Nat Commun, 15:7707-7707, 2024 Cited by PubMed 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. PubMed: 39300082DOI: 10.1038/s41467-024-51889-3 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.5 Å) |
Structure validation
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