8UDC
Crystal structure of TcPINK1 in complex with CYC116
Summary for 8UDC
| Entry DOI | 10.2210/pdb8udc/pdb |
| Related | 8UCT |
| Descriptor | Serine/threonine-protein kinase Pink1, mitochondrial, DI(HYDROXYETHYL)ETHER, SULFATE ION, ... (5 entities in total) |
| Functional Keywords | mitophagy autophagy kinase, cell cycle |
| Biological source | Tribolium castaneum (red flour beetle) |
| Total number of polymer chains | 1 |
| Total formula weight | 51468.76 |
| Authors | Veyron, S.,Rasool, S.,Trempe, J.F. (deposition date: 2023-09-28, release date: 2024-04-17, Last modification date: 2024-10-30) |
| Primary citation | Rasool, S.,Shomali, T.,Truong, L.,Croteau, N.,Veyron, S.,Bustillos, B.A.,Springer, W.,Fiesel, F.C.,Trempe, J.F. Identification and structural characterization of small molecule inhibitors of PINK1. Sci Rep, 14:7739-7739, 2024 Cited by PubMed Abstract: Mutations in PINK1 and Parkin cause early-onset Parkinson's Disease (PD). PINK1 is a kinase which functions as a mitochondrial damage sensor and initiates mitochondrial quality control by accumulating on the damaged organelle. There, it phosphorylates ubiquitin, which in turn recruits and activates Parkin, an E3 ubiquitin ligase. Ubiquitylation of mitochondrial proteins leads to the autophagic degradation of the damaged organelle. Pharmacological modulation of PINK1 constitutes an appealing avenue to study its physiological function and develop therapeutics. In this study, we used a thermal shift assay with insect PINK1 to identify small molecules that inhibit ATP hydrolysis and ubiquitin phosphorylation. PRT062607, an SYK inhibitor, is the most potent inhibitor in our screen and inhibits both insect and human PINK1, with an IC in the 0.5-3 µM range in HeLa cells and dopaminergic neurons. The crystal structures of insect PINK1 bound to PRT062607 or CYC116 reveal how the compounds interact with the ATP-binding pocket. PRT062607 notably engages with the catalytic aspartate and causes a destabilization of insert-2 at the autophosphorylation dimer interface. While PRT062607 is not selective for PINK1, it provides a scaffold for the development of more selective and potent inhibitors of PINK1 that could be used as chemical probes. PubMed: 38565869DOI: 10.1038/s41598-024-58285-3 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.1 Å) |
Structure validation
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