4AZE
Human DYRK1A in complex with Leucettine L41
Summary for 4AZE
| Entry DOI | 10.2210/pdb4aze/pdb |
| Related | 2VX3 2WO6 4AZF |
| Descriptor | DUAL SPECIFICITY TYROSINE-PHOSPHORYLATION-REGULATED KINASE 1A, 5-(1,3-benzodioxol-5-ylmethyl)-2-(phenylamino)-4H-imidazol-4-one (3 entities in total) |
| Functional Keywords | transferase |
| Biological source | HOMO SAPIENS (HUMAN) More |
| Cellular location | Nucleus speckle: Q13627 |
| Total number of polymer chains | 6 |
| Total formula weight | 136142.56 |
| Authors | Elkins, J.M.,Soundararajan, M.,Muniz, J.R.C.,Tahtouh, T.,Burgy, G.,Durieu, E.,Lozach, O.,Cochet, C.,Schmid, R.S.,Lo, D.C.,Delhommel, F.,Carreaux, F.,Bazureau, J.P.,Meijer, L.,Edwards, A.,Bountra, C.,Knapp, S. (deposition date: 2012-06-25, release date: 2012-09-05, Last modification date: 2023-12-20) |
| Primary citation | Tahtouh, T.,Elkins, J.M.,Filippakopoulos, P.,Soundararajan, M.,Burgy, G.,Durieu, E.,Cochet, C.,Schmid, R.S.,Lo, D.C.,Delhommel, F.,Oberholzer, A.,Laurence, P.,Carreaux, F.,Bazureau, J.P.,Knapp, S.,Meijer, L. Selectivity, Co-Crystal Structures and Neuroprotective Properties of Leucettines, a Family of Protein Kinase Inhibitors Derived from the Marine Sponge Alkaloid Leucettamine B. J.Med.Chem., 55:9312-, 2012 Cited by PubMed Abstract: DYRKs (dual specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases) are implicated in the onset and development of Alzheimer's disease and Down syndrome. The marine sponge alkaloid leucettamine B was recently identified as an inhibitor of DYRKs/CLKs. Synthesis of analogues (leucettines) led to an optimized product, leucettine L41. Leucettines were cocrystallized with DYRK1A, DYRK2, CLK3, PIM1, and GSK-3β. The selectivity of L41 was studied by activity and interaction assays of recombinant kinases and affinity chromatography and competition affinity assays. These approaches revealed unexpected potential secondary targets such as CK2, SLK, and the lipid kinase PIKfyve/Vac14/Fig4. L41 displayed neuroprotective effects on glutamate-induced HT22 cell death. L41 also reduced amyloid precursor protein-induced cell death in cultured rat brain slices. The unusual multitarget selectivity of leucettines may account for their neuroprotective effects. This family of kinase inhibitors deserves further optimization as potential therapeutics against neurodegenerative diseases such as Alzheimer's disease. PubMed: 22998443DOI: 10.1021/JM301034U PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.15 Å) |
Structure validation
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