8W318W31 の概要
| エントリーDOI | 10.2210/pdb8w31/pdb |
| 関連するPDBエントリー | 7US1 |
| 分子名称 | E3 ubiquitin-protein ligase parkin, Ubiquitin, ZINC ION, ... (6 entities in total) |
| 機能のキーワード | e3-ubiquitin ligase, ligase, activator |
| 由来する生物種 | Rattus norvegicus (Norway rat) 詳細 |
| タンパク質・核酸の鎖数 | 3 |
| 化学式量合計 | 44580.85 |
| 構造登録者 | |
| 主引用文献 | 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 主引用文献が同じPDBエントリー |
| 実験手法 | X-RAY DIFFRACTION (2.5 Å) |
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