8UDC

Crystal structure of TcPINK1 in complex with CYC116

8UDC の概要

• エントリーDOI: 10.2210/pdb8udc/pdb
• 関連するPDBエントリー: 8UCT
• 分子名称: Serine/threonine-protein kinase Pink1, mitochondrial, DI(HYDROXYETHYL)ETHER, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: mitophagy autophagy kinase, cell cycle
• 由来する生物種: Tribolium castaneum (red flour beetle)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 51468.76

構造登録者

Veyron, S.,Rasool, S.,Trempe, J.F. (登録日: 2023-09-28, 公開日: 2024-04-17, 最終更新日: 2024-10-30)

主引用文献

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

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: 38565869
DOI: 10.1038/s41598-024-58285-3

実験手法

X-RAY DIFFRACTION (3.1 Å)