Summary for 9EZ3
| Entry DOI | 10.2210/pdb9ez3/pdb |
| Descriptor | 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) |
| Functional Keywords | clk3, kinase, inhibitor, typii, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 43098.21 |
| Authors | Kraemer, A.,Raig, N.,Knapp, S. (deposition date: 2024-04-10, release date: 2024-09-11, Last modification date: 2025-09-24) |
| Primary citation | 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 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.7 Å) |
Structure validation
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