9EZ39EZ3 の概要
| エントリーDOI | 10.2210/pdb9ez3/pdb |
| 分子名称 | Dual specificity protein kinase CLK3, SULFATE ION, 1-(5-~{tert}-butyl-2-quinolin-6-yl-pyrazol-3-yl)-3-[3-(4-morpholin-4-yl-7~{H}-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl]urea (3 entities in total) |
| 機能のキーワード | clk3, kinase, inhibitor, typii, transferase |
| 由来する生物種 | Homo sapiens (human) |
| タンパク質・核酸の鎖数 | 1 |
| 化学式量合計 | 43098.21 |
| 構造登録者 | |
| 主引用文献 | Raig, N.D.,Surridge, K.J.,Sanz-Murillo, M.,Dederer, V.,Kramer, A.,Schwalm, M.P.,Lattal, N.M.,Elson, L.,Chatterjee, D.,Mathea, S.,Hanke, T.,Leschziner, A.E.,Reck-Peterson, S.L.,Knapp, S. Type II kinase inhibitors that target Parkinson's disease-associated LRRK2. Sci Adv, 11:eadt2050-eadt2050, 2025 Cited by PubMed Abstract: Increased kinase activity of leucine-rich repeat kinase 2 (LRRK2) is associated with Parkinson's disease (PD). Numerous LRRK2-selective type I kinase inhibitors have been developed, and some have entered clinical trials. Here, to our knowledge, we present the first type II kinase inhibitors that target LRRK2. Targeting the inactive conformation of LRRK2 is functionally distinct from targeting the active-like conformation using type I inhibitors. We designed these inhibitors with a combinatorial chemistry approach fusing selective LRRK2 type I and promiscuous type II inhibitors using iterative cycles of synthesis supported by structural biology and activity testing. Our lead compounds are selective and potent toward both LRRK2 and LRRK1, a close relative of LRRK2. Through cellular assays, cryo-electron microscopy structural analysis, and in vitro motility assays, we show that our inhibitors stabilize the open, inactive LRRK2 kinase conformation. These new conformation-specific compounds will be invaluable as tools to study LRRK2's function and regulation and expand the potential therapeutic options for PD. PubMed: 40465731DOI: 10.1126/sciadv.adt2050 主引用文献が同じPDBエントリー |
| 実験手法 | X-RAY DIFFRACTION (2.7 Å) |
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